The WAVE complex in developmental and adulthood brain disorders

Specific nuclear events and gene transcription are regulated by the availability of monomeric actin, since various nuclear proteins, such as chromatin remodeling complexes, histone modifiers and RNA polymerases, require monomeric actin for their activity.

“Notably, specific nuclear events and gene transcription are regulated by the availability of monomeric actin, since various nuclear proteins, such as chromatin remodeling complexes88, histone modifiers89 and RNA polymerases90,91, require monomeric actin for their activity.”

• cites [88] Kapoor, P. & Shen, X. Mechanisms of nuclear actin in chromatin-remodeling complexes. Trends Cell Biol. 24, 238–246 (2014). sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites [89] Serebryannyy, L. A., Cruz, C. M. & de Lanerolle, P. A role for nuclear actin in HDAC 1 and 2 regulation. Sci. Rep. 6, 28460 (2016). sourceDisputed

  Split into 2 atoms — 0 confirmed, 1 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured
• cites [90] Hofmann, W. A. et al. Actin is part of pre-initiation complexes and is necessary for transcription by RNA polymerase II. Nat. Cell Biol. 6, 1094–1101 (2004). sourceNot checked — no full text of the source

Upon stimulation of dopamine D1 receptors or NMDA glutamate receptors in brain slices, cAMP and calcium signaling and downstream PP2A and PP2B dephosphorylate WAVE1, indicating the critical involvement of protein phosphatases in neuronal activity-induced WAVE1 activation.

“Upon stimulation of dopamine D1 receptors (DRD1) or NMDA glutamate receptors in brain slices, cAMP and calcium signaling and downstream protein phosphatase-2A (PP2A) and PP2B dephosphorylate WAVE1, indicating the critical involvement of protein phosphatases in neuronal activity-induced WAVE1 activation44 (Figs. 2 and 3a).”

• cites [44] Ceglia, I., Kim, Y., Nairn, A. C. & Greengard, P. Signaling pathways controlling the phosphorylation state of WAVE1, a regulator of actin polymerization. J. Neurochem. 114, 182–190 (2010). sourceSupported

Phosphorylation of WAVE2 at Ser137 by CDK5 in the meander region is required for PDGF-induced oligodendrocyte precursor cell migration in vitro.

“Phosphorylation of WAVE2 at Ser137 by cyclin-dependent kinase 5 (CDK5) in the meander region is required for PDGF-induced oligodendrocyte precursor cell migration in vitro40.”

• cites [40] Miyamoto, Y., Yamauchi, J. & Tanoue, A. Cdk5 phosphorylation of WAVE2 regulates oligodendrocyte precursor cell migration through nonreceptor tyrosine kinase Fyn. J. Neurosci. 28, 8326–8337 (2008). sourcePartly supported

  The Results section on Cdk5 phosphorylation of WAVE2 reports that the nonphosphorylatable S137A mutant impaired PDGF-induced OPC migration in cultured cells. The Discussion identifies Ser-137 within WAVE2’s SH domain, but our copy does not identify it as being in a “meander region.” (LLM, conf=0.88)

  Experimental — accuracy not yet measured

WAVE1 is a brain-enriched regulator that is especially abundant in neurons, oligodendrocyte precursor cells and mature oligodendrocytes.

“WAVE1 is a brain-enriched regulator that is especially abundant in neurons9–12, oligodendrocyte precursor cells and mature oligodendrocytes13.”

• cites [9] Dahl, J. P. et al. Characterization of the WAVE1 knock-out mouse: implications for CNS development. J. Neurosci. 23, 3343–3352 (2003). sourceSupported
• cites [10] Soderling, S. H. et al. Loss of WAVE-1 causes sensorimotor retardation and reduced learning and memory in mice. Proc. Natl Acad. Sci. USA 100, 1723–1728 (2003). sourceSupported
• cites [11] Ceglia, I. et al. WAVE1 in neurons expressing the D1 dopamine receptor regulates cellular and behavioral actions of cocaine. Proc. Natl Acad. Sci. USA 114, 1395–1400 (2017). sourceSupported
• cites [12] Sossey-Alaoui, K., Head, K., Nowak, N. & Cowell, J. K. Genomic organization and expression profile of the human and mouse WAVE gene family. Mamm. Genome 14, 314–322 (2003). sourceNot checked — no full text of the source
• cites [13] Kim, H. J. et al. WAVE1 is required for oligodendrocyte morphogenesis and normal CNS myelination. J. Neurosci. 26, 5849–5859 (2006). sourceSupported

Rac1 binds to two sites on CYFIP in the WAVE complex, leading to WAVE activation.

“Rac1 binds to two sites on CYFIP in the WAVE complex, leading to WAVE activation28,30–32.”

• cites [28] Chen, B. et al. The WAVE regulatory complex links diverse receptors to the actin cytoskeleton. Cell 156, 195–207 (2014). sourcePartly supported

  The Introduction identifies Sra1 as CYFIP1 and says Rac binds Sra1 and activates the WAVE regulatory complex by releasing WAVE's inhibited VCA region. The Results also show Rac1 stimulating complex activity. Neither passage establishes the claim that Rac1 binds at two sites on CYFIP. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [30] Ding, B. et al. Structures reveal a key mechanism of WAVE regulatory complex activation by Rac1 GTPase. Nat. Commun. 13, 5444 (2022). sourceSupported
• cites [31] Kobayashi, K. et al. p140Sra-1 (specifically Rac1-associated protein) is a novel specific target for Rac1 small GTPase. J. Biol. Chem. 273, 291–295 (1998). sourcePartly supported

  The Abstract reports that activated Rac1 directly interacts with Sra-1 and identifies its N-terminal domain as responsible for binding. It does not identify Sra-1 as CYFIP or report two Rac1-binding sites, a WAVE complex, or WAVE activation; the Results and Discussion instead discuss a possible role in membrane ruffling. Page numbers were not available in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [32] Schaks, M. et al. Distinct interaction sites of Rac GTPase with WAVE regulatory complex have non-redundant functions in vivo. Curr. Biol. 28, 3674–3684.e3676 (2018). sourcePartly supported

  The Results and Discussion section identifies two Rac-binding sites on Sra-1/CYFIP and says Rac binding releases the WAVE WCA domain, enabling activation. It also finds that the A site is crucial for allosteric activation, whereas the D site is dispensable for activation. The claim is therefore supported on binding and activation generally, but not if it implies that binding at both sites drives activation. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

WAVE proteins exist as heteropentameric complexes together with regulatory proteins including CYFIP, NCKAP, ABI and BRK1 (specifically NCKAP1/1L, CYFIP1/2, ABI1/2/3, and BRK1).

“WAVE proteins exist as heteropentameric complexes together with regulatory proteins, including CYFIP, NCKAP, ABI and BRK1.”

• Also stated in: § Introduction · plain

  “WAVE proteins exist as heteropentameric protein complexes, termed the WAVE complex19,20 or WAVE regulatory complex21, together with NCK-associated protein 1 (NCKAP1) or NCK-associated protein 1-like (NCKAP1L), cytoplasmic FMR1 interacting protein (CYFIP) 1 or 2, ABL-interactor (ABI) 1, 2 or 3, and BRK1 (also called HSPC300)11,19,22,23.”

• cites [19] Eden, S., Rohatgi, R., Podtelejnikov, A. V., Mann, M. & Kirschner, M. W. Mechanism of regulation of WAVE1-induced actin nucleation by Rac1 and Nck. Nature 418, 790–793 (2002). sourceNot checked — no full text of the source
• cites [20] Lebensohn, A. M. & Kirschner, M. W. Activation of the WAVE complex by coincident signals controls actin assembly. Mol. Cell 36, 512–524 (2009). sourceSupported
• cites [21] Chen, Z. et al. Structure and control of the actin regulatory WAVE complex. Nature 468, 533–538 (2010). sourceSupported

Phosphorylation of WAVE or ABI mediates the activation or inhibition of the WAVE complex, depending on specific phosphorylation sites.

“The phosphorylation of WAVE or ABI mediates the activation or inhibition of the WAVE complex, depending on specific phosphorylation sites22,36 (Figs. 2 and 3).”

• cites [22] Kim, Y. et al. Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology. Nature 442, 814–817 (2006). sourceNot checked — no full text of the source
• cites [36] Mendoza, M. C. Phosphoregulation of the WAVE regulatory complex and signal integration. Semin. Cell Dev. Biol. 24, 272–279 (2013). sourceSupported

These ERK or JNK phosphorylation sites are not present in WAVE1 or WAVE3.

“However, these ERK or JNK phosphorylation sites are not present in WAVE1 or WAVE336.”

• cites [36] Mendoza, M. C. Phosphoregulation of the WAVE regulatory complex and signal integration. Semin. Cell Dev. Biol. 24, 272–279 (2013). sourcePartly supported

  Section 3.2 (ERK; page unavailable) states that the listed WAVE2 ERK phosphorylation sites are absent from WAVE1 and WAVE3. Our copy does not identify these as JNK phosphorylation sites or establish the corresponding claim for JNK. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

WAVE members are key activators of ARP2/3 complex-mediated actin polymerization.

“Wiskott‒Aldrich syndrome protein-family verprolin-homologous protein (WAVE) members are key activators of ARP2/3 complex-mediated actin polymerization.”

• cites [7] Campellone, K. G., Lebek, N. M. & King, V. L. Branching out in different directions: emerging cellular functions for the Arp2/3 complex and WASP-family actin nucleation factors. Eur. J. Cell Biol. 102, 151301 (2023). sourceSupported
• cites [8] Kramer, D. A., Piper, H. K. & Chen, B. WASP family proteins: molecular mechanisms and implications in human disease. Eur. J. Cell Biol. 101, 151244 (2022). sourceSupported

Compared with their paralogs, WAVE1, CYFIP2, NCKAP1 and ABI2 are relatively abundant in the brain.

“Compared with their paralogs, WAVE1, CYFIP2, NCKAP1 and ABI2 are relatively abundant in the brain19,20,22 (Fig. 1).”

• cites [19] Eden, S., Rohatgi, R., Podtelejnikov, A. V., Mann, M. & Kirschner, M. W. Mechanism of regulation of WAVE1-induced actin nucleation by Rac1 and Nck. Nature 418, 790–793 (2002). sourceNot checked — no full text of the source
• cites [20] Lebensohn, A. M. & Kirschner, M. W. Activation of the WAVE complex by coincident signals controls actin assembly. Mol. Cell 36, 512–524 (2009). sourceCould not verify

  The Results section (‘Native WAVE complexes are basally inactive’) says the authors purified WAVE1 complexes from bovine brain and notes that WAVE1 and WAVE2 have different expression patterns. It does not compare brain abundance with paralogs for WAVE1, CYFIP2, NCKAP1, or ABI2; searches for brain expression and those subunits found no such comparison. Page numbers were not available in our copy. (LLM, conf=0.75)

  Experimental — accuracy not yet measured
• cites [22] Kim, Y. et al. Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology. Nature 442, 814–817 (2006). sourceNot checked — no full text of the source

The availability of the WCA region of WAVE for ARP2/3 activation is hindered by multiple interactions with both CYFIP and the "meander" region of WAVE.

“The availability of the WCA region of WAVE for ARP2/3 activation is hindered by multiple interactions with both CYFIP and the “meander” region of WAVE21 (Fig. 2).”

• cites [21] Chen, Z. et al. Structure and control of the actin regulatory WAVE complex. Nature 468, 533–538 (2010). sourceSupported

In cultured rat cortical neurons, the phosphorylation of WAVE1 at Ser310, Ser397 and Ser441 was acutely increased by estrogen treatment.

“In cultured rat cortical neurons, the phosphorylation of WAVE1 at Ser310, Ser397 and Ser441 was acutely increased by estrogen treatment46.”

• cites [46] Sanchez, A. M. et al. Rapid signaling of estrogen to WAVE1 and moesin controls neuronal spine formation via the actin cytoskeleton. Mol. Endocrinol. 23, 1193–1202 (2009). sourceSupported

Acidic phospholipids such as PIP3 or PI(4,5)P2 bind to the basic surface of WAVE2 complexes, enhancing WAVE2 complex activation via prenylated Rac1.

“Acidic phospholipids such as phosphatidylinositol (3,4,5)-triphosphate (PIP3) or PI(4,5)P2 bind to the basic surface of WAVE2 complexes, enhancing WAVE2 complex activation via prenylated Rac120 (Fig. 2).”

• cites [20] Lebensohn, A. M. & Kirschner, M. W. Activation of the WAVE complex by coincident signals controls actin assembly. Mol. Cell 36, 512–524 (2009). sourcePartly supported

  The Results sections on cooperative activation and binding report that PIP3 and PI(4,5)P2 support WAVE2-complex activation with prenylated Rac1-GTP, and that acidic lipids bind the complex. They do not identify a basic surface of the complex as the lipid-binding site; the copy also specifies the GTP-bound state of Rac1, which the claim omits. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

In primary cultured cortical neurons, repetitive depolarization by KCl induces WAVE1 dephosphorylation in an NMDA receptor-dependent manner.

“In primary cultured cortical neurons, repetitive depolarization by KCl induces WAVE1 dephosphorylation in an NMDA receptor-dependent manner45.”

• cites [45] Sung, J. Y. et al. WAVE1 controls neuronal activity-induced mitochondrial distribution in dendritic spines. Proc. Natl Acad. Sci. USA 105, 3112–3116 (2008). sourceSupported

CK2 phosphorylates Ser482, 484, 488, 489 and 497 within the acidic region of the WCA domain of WAVE2.

“Casein kinase 2 (CK2) phosphorylates Ser482, 484, 488, 489 and 497 within the acidic region of the WCA domain of WAVE248.”

• cites [48] Pocha, S. M. & Cory, G. O. WAVE2 is regulated by multiple phosphorylation events within its VCA domain. Cell Motil. Cytoskeleton 66, 36–47 (2009). sourceSupported

Compared with WT oligodendrocytes, primary cultured oligodendrocytes isolated from WAVE1 knockout mice exhibit fewer processes.

“Compared with WT oligodendrocytes, primary cultured oligodendrocytes isolated from WAVE1 knockout (KO) mice exhibit fewer processes.”

• cites [13] Kim, H. J. et al. WAVE1 is required for oligodendrocyte morphogenesis and normal CNS myelination. J. Neurosci. 26, 5849–5859 (2006). sourceSupported

ERK also phosphorylates multiple sites in ABI1, including Ser183, Ser216, Ser225, Thr265, Ser267, Ser392, Thr394 and Ser410.

“ERK also phosphorylates multiple sites in ABI1, including Ser183, Ser216, Ser225, Thr265, Ser267, Ser392, Thr394 and Ser41041 (Fig. 3d).”

• cites [41] Mendoza, M. C. et al. ERK-MAPK drives lamellipodia protrusion by activating the WAVE2 regulatory complex. Mol. Cell 41, 661–671 (2011). sourcePartly supported

  The Results section reports ERK-dependent phosphorylation of Abi1 and shows that mutating all eight listed sites nearly abolished phosphorylation by ERK2. But it directly identifies S183 and S225, calls S216 suspected rather than definitive, and describes T265, S267, S392, T394 and S410 as predicted ERK sites. The evidence therefore supports the group-level claim more strongly than it establishes phosphorylation at each named site. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

The BDNF-RAC1-CYFIP1 pathway can increase both the local protein translation and actin polymerization required for synaptic plasticity.

“Thus, the BDNF-RAC1-CYFIP1 pathway can increase both the local protein translation and actin polymerization required for synaptic plasticity66,69.”

• cites [66] De Rubeis, S. et al. CYFIP1 coordinates mRNA translation and cytoskeleton remodeling to ensure proper dendritic spine formation. Neuron 79, 1169–1182 (2013). sourceSupported
• cites [69] Napoli, I. et al. The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP. Cell 134, 1042–1054 (2008). sourcePartly supported

  The synapse experiments (p. 8) show that BDNF releases eIF4E from CYFIP1, consistent with increased local translation. The paper also links CYFIP1 to the actin-polymerizing WAVE complex (Discussion, p. 8), but it does not show that BDNF increases actin polymerization through a RAC1–CYFIP1 pathway; a RAC1 role in releasing translational repression is described as speculation (p. 9). (LLM, conf=0.86)

  Experimental — accuracy not yet measured

WAVE1 is highly expressed in oligodendrocytes.

“WAVE1 is highly expressed in oligodendrocytes13.”

• cites [13] Kim, H. J. et al. WAVE1 is required for oligodendrocyte morphogenesis and normal CNS myelination. J. Neurosci. 26, 5849–5859 (2006). sourceSupported

Haploinsufficiency of Cyfip1 causes abnormal migration of adult-born neurons due to altered ARP2/3-mediated actin dynamics.

“In addition, haploinsufficiency of Cyfip1 causes abnormal migration of adult-born neurons due to altered ARP2/3-mediated actin dynamics76.”

• cites [76] Haan, N. et al. Haploinsufficiency of the schizophrenia and autism risk gene Cyfip1 causes abnormal postnatal hippocampal neurogenesis through microglial and Arp2/3 mediated actin dependent mechanisms. Transl. Psychiatry 11, 313 (2021). sourceSupported

CYFIP1 also regulates adult hippocampal neurogenesis via cell-autonomous and non-cell-autonomous mechanisms.

“CYFIP1 also regulates adult hippocampal neurogenesis via cell-autonomous and non-cell-autonomous mechanisms76.”

• cites [76] Haan, N. et al. Haploinsufficiency of the schizophrenia and autism risk gene Cyfip1 causes abnormal postnatal hippocampal neurogenesis through microglial and Arp2/3 mediated actin dependent mechanisms. Transl. Psychiatry 11, 313 (2021). sourceSupported

CYFIP1/Sra1 directly binds to eIF4E and thereby inhibits translational initiation.

“CYFIP1/Sra1 directly binds to eIF4E (eukaryotic translation initiation factor 4E) and thereby inhibits translational initiation69.”

• cites [69] Napoli, I. et al. The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP. Cell 134, 1042–1054 (2008). sourceSupported

Experiments with proteins containing mutations of these sites implicate a role of ABI1 phosphorylation in the release of the WCA domain and subsequent WAVE complex activation.

“Experiments with proteins containing mutations of these sites implicate a role of ABI1 phosphorylation in the release of the WCA domain and subsequent WAVE complex activation36,41.”

• cites [36] Mendoza, M. C. Phosphoregulation of the WAVE regulatory complex and signal integration. Semin. Cell Dev. Biol. 24, 272–279 (2013). sourceSupported
• cites [41] Mendoza, M. C. et al. ERK-MAPK drives lamellipodia protrusion by activating the WAVE2 regulatory complex. Mol. Cell 41, 661–671 (2011). sourcePartly supported

  The Results and Discussion report that mutations of Abi1 phosphorylation sites reduce WRC interaction with Arp2/3 and actin, supporting a role for Abi1 phosphorylation in WRC function. They do not show that Abi1 phosphorylation releases the WCA domain. The Introduction discusses release of the related VCA domain in connection with Rac binding and Abl phosphorylation of WAVE2, not Abi1 phosphorylation; page numbers are unavailable in our copy. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

Upon NMDA application, ABI1 translocates from PSDs to nuclei in primary cultured hippocampal neurons and in pyramidal neurons in acute rat brain slices.

“Upon NMDA application, ABI1 translocates from PSDs to nuclei in primary cultured hippocampal neurons and in pyramidal neurons in acute rat brain slices50.”

• cites [50] Proepper, C. et al. Abelson interacting protein 1 (Abi-1) is essential for dendrite morphogenesis and synapse formation. EMBO J. 26, 1397–1409 (2007). sourceSupported

CYFIP1 is involved in distinct FMRP-CYFIP1-eIF4E and WAVE complex functions and thereby coordinates local protein translation and actin polymerization in dendritic spines.

“Thus, CYFIP1 is involved in distinct FMRP-CYFIP1-eIF4E and WAVE complex functions and thereby coordinates local protein translation and actin polymerization in dendritic spines66,69,70.”

• cites [66] De Rubeis, S. et al. CYFIP1 coordinates mRNA translation and cytoskeleton remodeling to ensure proper dendritic spine formation. Neuron 79, 1169–1182 (2013). sourceSupported
• cites [69] Napoli, I. et al. The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP. Cell 134, 1042–1054 (2008). sourcePartly supported

  The Discussion (p. 8) identifies CYFIP1 as both an FMRP-interacting factor and a component of the actin-related WAVE complex, while the synaptic experiments (p. 8) support its role in regulating translation through FMRP and eIF4E. The paper does not establish that CYFIP1 coordinates translation and actin polymerization in dendritic spines; the Relevance for the Fragile X Syndrome section (p. 10) only proposes a connection to synapse maturation. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [70] Abekhoukh, S. et al. New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes. Dis. Model Mech. 10, 463–474 (2017). sourcePartly supported

  The Introduction describes CYFIP1’s roles in the WAVE complex and in translational regulation with FMRP and eIF4E. The Discussion (Functional significance of the FMRP-CYFIP interaction) proposes that CYFIP1 might link FMRP to actin remodeling and coordinate these processes, while the spine-morphology discussion considers altered actin dynamics and/or translational regulation as possible explanations for smaller spine heads. The source does not establish that CYFIP1 coordinates local protein translation and actin polymerization in dendritic spines; it presents that mechanistic connection as a hypothesis. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

In the brain, focal ischemic stroke induces the formation of a protein complex of WAVE1, pancortin-2 and the antiapoptotic protein Bcl-xL.

“In the brain, focal ischemic stroke induces the formation of a protein complex of WAVE1, pancortin-2 and the antiapoptotic protein Bcl-xL.”

• cites [83] Cheng, A. et al. Pancortin-2 interacts with WAVE1 and Bcl-xL in a mitochondria-associated protein complex that mediates ischemic neuronal death. J. Neurosci. 27, 1519–1528 (2007). sourceSupported

Many transmembrane cell adhesion molecules and receptors, including protocadherins, ROBOs, netrin receptors, neuroligins, GPCRs and ion channels, may recruit the WAVE complex to membranes via the interaction of CYFIP and ABI with a conserved motif called WIRS.

“In addition to RAC (or ARF) and acidic phospholipids (PIP2 or PIP3), many transmembrane cell adhesion molecules and receptors, including protocadherins, ROBOs, netrin receptors, neuroligins, GPCRs and ion channels, may recruit the WAVE complex to membranes via the interaction of CYFIP and ABI with a conserved motif called WIRS (WAVE complex interacting receptor sequence)23,28 (Fig. 2).”

• cites [23] Han, K. A. & Ko, J. Orchestration of synaptic functions by WAVE regulatory complex-mediated actin reorganization. Exp. Mol. Med. 55, 1065–1075 (2023). sourcePartly supported

  The section on transduction of extracellular synaptic adhesion signals says that WIRS binds a surface formed by CYFIP and ABI and suggests that WIRS-containing adhesion molecules help recruit the WRC to membranes. Table 1 lists WIRS motifs in protocadherins, ROBOs, netrin receptors, neuroligins and adhesion GPCRs; Fig. 2 likewise describes possible WIRS-mediated recruitment by several receptors. Our copy does not identify ion channels as WIRS-containing recruiters, so that example is unsupported. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [28] Chen, B. et al. The WAVE regulatory complex links diverse receptors to the actin cytoskeleton. Cell 156, 195–207 (2014). sourceSupported

CYFIP2 regulates presynaptic functions presumably via the regulation of presynaptic mitochondria number in the adult brain.

“CYFIP2 regulates presynaptic functions presumably via the regulation of presynaptic mitochondria number in the adult brain74.”

• cites [74] Kim, G. H. et al. Altered presynaptic function and number of mitochondria in the medial prefrontal cortex of adult Cyfip2 heterozygous mice. Mol. Brain 13, 123 (2020). sourcePartly supported

  The Main text reports altered presynaptic short-term plasticity and fewer presynaptic mitochondria in layer 5 of the medial prefrontal cortex of adult Cyfip2 heterozygous mice. It speculates that the reduced mitochondrial number may contribute to the functional change, consistent with the claim’s hedge, but does not establish this mechanism across the adult brain. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

CYFIP1 plays a role in determining the presynaptic terminal size and vesicle release probability during development.

“CYFIP1 plays a role in determining the presynaptic terminal size and vesicle release probability during development73.”

• cites [73] Hsiao, K., Harony-Nicolas, H., Buxbaum, J. D., Bozdagi-Gunal, O. & Benson, D. L. Cyfip1 regulates presynaptic activity during development. J. Neurosci. 36, 1564–1576 (2016). sourceSupported

Haploinsufficiency of mouse Cyfip1 results in increased numbers of adult-born hippocampal neurons due to reduced apoptosis without altering proliferation via a failure of microglia to induce apoptosis through the secretion of appropriate factors.

“Haploinsufficiency of mouse Cyfip1 results in increased numbers of adult-born hippocampal neurons due to reduced apoptosis without altering proliferation via a failure of microglia to induce apoptosis through the secretion of appropriate factors76.”

• cites [76] Haan, N. et al. Haploinsufficiency of the schizophrenia and autism risk gene Cyfip1 causes abnormal postnatal hippocampal neurogenesis through microglial and Arp2/3 mediated actin dependent mechanisms. Transl. Psychiatry 11, 313 (2021). sourceSupported

CYFIP1 is required for neural stem cell activity in the subventricular zone and maintenance of the neurogenic niche of the lateral ventricles and thereby cortical neurogenesis in adult mice.

“CYFIP1 is required for neural stem cell activity in the subventricular zone and maintenance of the neurogenic niche of the lateral ventricles and thereby cortical neurogenesis in adult mice75 (Fig. 4a).”

• cites [75] Habela, C. W. et al. Persistent Cyfip1 expression is required to maintain the adult subventricular zone neurogenic niche. J. Neurosci. 40, 2015–2024 (2020). sourcePartly supported

  The Abstract and Discussion (page numbers unavailable) support a role for Cyfip1 in adult mouse SVZ stem-cell behavior and maintenance of the lateral-ventricle neurogenic niche. They do not support the claimed consequence for cortical neurogenesis in adult mice: the Abstract places the cortical-neurogenesis effect during embryonic development, and the Discussion reports no immediate increase in neurogenesis after acute adult Cyfip1 loss. (LLM, conf=0.91)

  Experimental — accuracy not yet measured

WAVE1, together with the RAC GEF Dock3, were found to be downstream effectors of the BDNF-TRKB signaling cascade during axonal outgrowth.

“WAVE1, together with the RAC GEF Dock3, were found to be downstream effectors of the BDNF-TRKB signaling cascade during axonal outgrowth71.”

• cites [71] Namekata, K. et al. Dock3 induces axonal outgrowth by stimulating membrane recruitment of the WAVE complex. Proc. Natl Acad. Sci. USA 107, 7586–7591 (2010). sourceSupported

Treatment of cells with leptomycin B (an inhibitor of the nuclear exporter CRM-1) induces the nuclear accumulation of ABI1 and CYFIP2.

“Treatment of cells with leptomycin B (an inhibitor of the nuclear exporter CRM-1) induces the nuclear accumulation of ABI184 and CYFIP285.”

• cites [84] Echarri, A., Lai, M. J., Robinson, M. R. & Pendergast, A. M. Abl interactor 1 (Abi-1) wave-binding and SNARE domains regulate its nucleocytoplasmic shuttling, lamellipodium localization, and wave-1 levels. Mol. Cell Biol. 24, 4979–4993 (2004). sourceSupported
• cites [85] Jackson, R. S. 2nd, Cho, Y. J., Stein, S. & Liang, P. CYFIP2, a direct p53 target, is leptomycin-B sensitive. Cell Cycle 6, 95–103 (2007). sourceSupported

In primary cultured neurons, WAVE1-mediated actin polymerization is involved in neuronal activity-induced mitochondrial trafficking and fission.

“In primary cultured neurons, WAVE1-mediated actin polymerization is involved in neuronal activity-induced mitochondrial trafficking and fission45 (Fig. 4a).”

• cites [45] Sung, J. Y. et al. WAVE1 controls neuronal activity-induced mitochondrial distribution in dendritic spines. Proc. Natl Acad. Sci. USA 105, 3112–3116 (2008). sourcePartly supported

  The Results and Discussion support a role for WAVE1 in activity-induced mitochondrial trafficking to dendritic protrusions in cultured neurons. The Discussion describes mediation by WAVE1-dependent actin polymerization as likely, not established, and says depolarization-induced fission still occurred when WAVE1 expression was reduced. Page numbers are not available in our copy. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

WAVE1 also regulates growth cone dynamics and neurite outgrowth in cultured neurons.

“WAVE1 also regulates growth cone dynamics and neurite outgrowth in cultured neurons61 (Fig. 4a).”

• cites [61] Soderling, S. H. et al. A WAVE-1 and WRP signaling complex regulates spine density, synaptic plasticity, and memory. J. Neurosci. 27, 355–365 (2007). sourceSupported

WAVE1, a downstream effector of NMDA receptor signaling, is a critical mediator of cognitive function.

“WAVE1, a downstream effector of NMDA receptor signaling44, is a critical mediator of cognitive function.”

• cites [44] Ceglia, I., Kim, Y., Nairn, A. C. & Greengard, P. Signaling pathways controlling the phosphorylation state of WAVE1, a regulator of actin polymerization. J. Neurochem. 114, 182–190 (2010). sourceSupported

An amino acid in-frame deletion p.Val305del in CYFIP1 was identified in a patient with West syndrome characterized by infantile intellectual disability, epilepsy, and autism spectrum disorder.

“Furthermore, an amino acid in-frame deletion, p.Val305del, was identified in a patient with West syndrome, who was characterized by infantile ID, epilepsy, and ASD116 (Table 2o).”

• cites [116] Peng, J. et al. Novel West syndrome candidate genes in a Chinese cohort. CNS Neurosci. Ther. 24, 1196–1206 (2018). sourcePartly supported

  Table 1 lists a de novo in-frame CYFIP1 deletion in patient WS46 with West syndrome, but records it as c.909_911del, p.303_304del—not p.Val305del. The passages do not establish that this patient had intellectual disability or ASD; the discussion links CYFIP1 to ASD generally, not to WS46’s clinical features. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Table 2oNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Compound heterozygous CYFIP1 variants p.Ile476Val and p.Pro742Leu were identified in two affected males from a family who exhibited developmental delay, intellectual disability, autism spectrum disorder, epilepsy, and absence of speech.

“Following the association of two common SNPs in CYFIP1 in SCZ patients110 (Table 2j), the compound heterozygous variants p.Ile476Val and p.Pro742Leu were identified via exome sequencing in two affected males from a family, who exhibited DD, ID, ASD, epilepsy, and an absence of speech (Table 2k).”

• cites [111] Mariano, V. et al. Intellectual disability and behavioral deficits linked to CYFIP1 missense variants disrupting actin polymerization. Biol. Psychiatry 95, 161–174 (2024). sourceSupported
• cites Table 2kNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The three truncated variants are associated with a similar phenotype as that observed in Wasf1 KO mice.

“Notably, the three truncated variants are associated with a similar phenotype as that observed in Wasf1 KO mice10.”

• cites [10] Soderling, S. H. et al. Loss of WAVE-1 causes sensorimotor retardation and reduced learning and memory in mice. Proc. Natl Acad. Sci. USA 100, 1723–1728 (2003). sourceSupported

Owing to the scarcity of reported loss-of-function variants, with only 17 cases (allele frequency: ~7E-7) in the Genome Aggregation Database from healthy subjects, the WASF1 gene exhibits exceptionally high intolerance to such mutations.

“Owing to the scarcity of reported loss-of-function (LoF) variants, with only 17 cases (allele frequency: ~7E-7) in the Genome Aggregation Database (gnomAD) from healthy subjects100, the WASF1 gene exhibits exceptionally high intolerance to such mutations.”

• cites [100] Karczewski, K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581, 434–443 (2020). sourcePartly supported

  The Abstract and the section 'Identifying loss-of-function variants' describe gnomAD’s catalogue of predicted loss-of-function variants, and the paper explains how depletion of those variants informs gene-level intolerance. Our copy does not report a WASF1-specific count of 17, an allele frequency near 7 × 10⁻⁷, or a WASF1 constraint result, so those particulars are not supported. (LLM, conf=0.77)

  Experimental — accuracy not yet measured

Ito et al. first identified three de novo heterozygous truncating variants clustered around the C-terminal WH2 domain in five unrelated individuals with overlapping neurodevelopmental phenotypes, including severe ID with autistic features and seizures.

“Ito et al. first identified three de novo heterozygous truncating variants clustered around the C-terminal WH2 domain in five unrelated individuals with overlapping neurodevelopmental phenotypes, including severe ID with autistic features and seizures93 (Table 2a).”

• cites [93] Ito, Y. et al. De novo truncating mutations in WASF1 cause intellectual disability with seizures. Am. J. Hum. Genet. 103, 144–153 (2018). sourceSupported

A nonsense WASF3 variant, p.Glu88Ter, was identified in a patient with neurodevelopmental disorders.

“A nonsense WASF3 variant, p.Glu88Ter, was identified in a patient with NDDs103,104,106 (Table 2h).”

• cites [103] Kaplanis, J. et al. Evidence for 28 genetic disorders discovered by combining healthcare and research data. Nature 586, 757–762 (2020). sourceCould not verify

  The Introduction discusses de novo variants in patients with developmental disorders, but the passages from our copy do not identify a WASF3 variant or a patient carrying p.Glu88Ter. Searches for “WASF3,” “Glu88Ter,” and the combined phrase found no passage addressing that specific claim. (LLM, conf=0.73)

  Experimental — accuracy not yet measured
• cites [104] Zhou, X. et al. Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes. Nat. Genet. 54, 1305–1319 (2022). sourceCould not verify

  The Results section discusses variants in genes including MARK2, ITSN1 and NAV3, but does not identify a WASF3 variant in a patient with a neurodevelopmental disorder. Searches of our copy for WASF3 and p.Glu88Ter found no passage addressing the claimed variant. (LLM, conf=0.72)

  Experimental — accuracy not yet measured
• cites [106] Turner, T. N. et al. Sex-based analysis of de novo variants in neurodevelopmental disorders. Am. J. Hum. Genet. 105, 1274–1285 (2019). sourceCould not verify

  The Results and Discussion passages describe de novo variants in patients with neurodevelopmental disorders, but none identifies a WASF3 variant in a patient. Searches of our copy for “WASF3,” “p.Glu88Ter,” and “Glu88Ter” found no passage addressing the specific nonsense variant. (LLM, conf=0.70)

  Experimental — accuracy not yet measured

Two common SNPs in CYFIP1 are associated with schizophrenia.

“Following the association of two common SNPs in CYFIP1 in SCZ patients110 (Table 2j), the compound heterozygous variants p.Ile476Val and p.Pro742Leu were identified via exome sequencing in two affected males from a family, who exhibited DD, ID, ASD, epilepsy, and an absence of speech (Table 2k).”

• cites [110] Zhao, Q. et al. Rare CNVs and tag SNPs at 15q11.2 are associated with schizophrenia in the Han Chinese population. Schizophr. Bull. 39, 712–719 (2013). sourcePartly supported

  The Associations Between Tag SNPs and Schizophrenia section reports an association for one common CYFIP1 SNP, rs1009153. Table 3 lists the other SNP that remained significant after permutation, rs4778334, between NIPA2 and NIPA1—not in CYFIP1. The claim's count of two CYFIP1 SNPs is therefore unsupported. (LLM, conf=0.92)

  Experimental — accuracy not yet measured
• cites Table 2jNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Among the four genes (TUBGCP5, CYFIP1, NIPA2, and NIPA1) in the 15q11.2 region, increasing evidence highlights the relevance of CYFIP1.

“Among the four genes (TUBGCP5, CYFIP1, NIPA2, and NIPA1) encompassed within this narrow region, increasing evidence highlights the relevance of CYFIP1109.”

• cites [109] Woo, Y. J. et al. Domain-specific cognitive impairments in humans and flies with reduced CYFIP1 dosage. Biol. Psychiatry 86, 306–314 (2019). sourceSupported

A probability of LoF intolerance score of 0.91 for WASF1 suggests that LoF is likely the underlying mechanism of the variant.

“In addition, a probability of LoF intolerance (pLI) score of 0.91 for WASF193 suggests that LoF is likely the underlying mechanism of the variant.”

• cites [93] Ito, Y. et al. De novo truncating mutations in WASF1 cause intellectual disability with seizures. Am. J. Hum. Genet. 103, 144–153 (2018). sourcePartly supported

  The Main Text reports that WASF1 is constrained for loss-of-function variation, with a pLI of 0.91. But it does not infer from that score that loss of function is the variant’s likely mechanism. Instead, it says the observed truncated protein suggests altered mutant-protein function rather than complete protein loss or haploinsufficiency. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

The WASF1 variant p.Lys172Glu was found in a patient with developmental delay, hypotonia, and autism.

“Additionally, the variant p.Trp161Cys was reported in a patient with ID, autism, hypotonia, and epilepsy, whereas p.Lys172Glu was found in a patient with DD, hypotonia, and autism95.”

• cites [95] Srivastava, S. et al. Expansion of the genotypic and phenotypic spectrum of WASF1-related neurodevelopmental disorder. Brain Sci. 11, https://doi.org/10.3390/brainsci11070931 (2021). sourcePartly supported

  Results §3.1 identifies p.K172E (p.Lys172Glu) in patient P4. Results §3.2 says P4 had global developmental delay and that all six patients had hypotonia. It describes autism as nearly universal in the cohort but does not establish whether P4 had autism. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Nuclear WAVE1 was identified as a central regulator of the transcriptional reprogramming required for Xenopus oocyte development.

“Nuclear WAVE1 was identified as a central regulator of the transcriptional reprogramming required for Xenopus oocyte development86.”

• cites [86] Miyamoto, K. et al. Nuclear Wave1 is required for reprogramming transcription in oocytes and for normal development. Science 341, 1002–1005 (2013). sourcePartly supported

  The paper reports that nuclear Wave1 is necessary for efficient transcriptional reprogramming in Xenopus oocytes (passage 2). It links Wave1 to normal embryonic development, however, rather than showing that this reprogramming is required for oocyte development (passages 1 and 5). (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Two missense WASF2 variants, c.113G > A (p.Arg38Gln) and c.494T > C (p.Leu165Pro), were identified in patients with autism and neurodevelopmental disorders.

“Two missense WASF2 variants, c.113G > A (p.Arg38Gln) and c.494T > C (p.Leu165Pro), were identified in patients with autism and NDDs103–105, but the functional alterations associated with brain disorders remain to be studied (Table 2g).”

• cites [103] Kaplanis, J. et al. Evidence for 28 genetic disorders discovered by combining healthcare and research data. Nature 586, 757–762 (2020). sourceCould not verify

  The Introduction’s discussion of missense variants in developmental disorders and the Extended Data table do not identify WASF2 or either specified variant. Searches of our copy for WASF2, Arg38Gln, Leu165Pro, and the variant notation returned no passage linking them to patients with autism or neurodevelopmental disorders. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [104] Zhou, X. et al. Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes. Nat. Genet. 54, 1305–1319 (2022). sourceCould not verify

  The Results passages describe analyses of autism and neurodevelopmental-disorder variants, but none identifies a WASF2 variant. Searches of our copy for WASF2 and the two specified missense substitutions found no passage reporting them in affected patients. (LLM, conf=0.70)

  Experimental — accuracy not yet measured
• cites [105] Tran Mau-Them, F. et al. Second-tier trio exome sequencing after negative solo clinical exome sequencing: an efficient strategy to increase diagnostic yield and decipher molecular bases in undiagnosed developmental disorders. Hum. Genet. 139, 1381–1390 (2020). sourceCould not verify

  The available indexed passages contain a reference-list entry for Tran Mau-Them et al. (2020), rather than findings from that paper; no section or page is provided. Searches for WASF2, both variant identifiers, and the protein changes found no passage addressing whether these variants were identified in patients with autism or neurodevelopmental disorders. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites Table 2gNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Four heterozygous missense CYFIP1 variants were identified in patients with autism spectrum disorder, including a common variant p.Gly820Ser and three rare variants p.Asp544Asn, p.Met956Arg, and p.Ala1025Thr.

“Four heterozygous missense CYFIP1 variants were identified in patients with ASD, including a common variant, p.Gly820Ser113 (Table 2l), and three rare variants, p.Asp544Asn, p.Met956Arg and p.Ala1025Thr114 (Table 2m).”

• cites [113] Waltes, R. et al. Common variants in genes of the postsynaptic FMRP signalling pathway are risk factors for autism spectrum disorders. Hum. Genet. 133, 781–792 (2014). sourceNot checked — no full text of the source
• cites [114] Fu, J. M. et al. Rare coding variation provides insight into the genetic architecture and phenotypic context of autism. Nat. Genet. 54, 1320–1331 (2022). sourceCould not verify

  The Results section, “Patterns of rare coding variants in ASD” (page unavailable), reports missense variants in ASD generally, but does not identify CYFIP1 variants. Searches for CYFIP1 and all four named substitutions found no passage in our copy confirming their identities, heterozygosity, or common versus rare status. (LLM, conf=0.74)

  Experimental — accuracy not yet measured
• cites Table 2lNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

CYFIP1 downregulation or genetic alterations in CYFIP1 might alter the FMRP-CYFIP1-eIF4E-mediated repression of local protein synthesis in neurons.

“CYFIP1 downregulation or genetic alterations in CYFIP1 might alter the FMRP-CYFIP1-eIF4E-mediated repression of local protein synthesis in neurons69.”

• cites [69] Napoli, I. et al. The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP. Cell 134, 1042–1054 (2008). sourceSupported

The p.Trp161Arg variant in WASF1, resulting from either c.481T > A or c.481T > C, causes similar phenotypes in two independent patients: intellectual disability, developmental delay, epilepsy, and microcephaly.

“The phenotypes of two independent patients, each carrying the p.Trp161Arg variant in WASF1 resulting from distinct genomic alterations—either c.481T > A95 or c.481T > C102—are similar, displaying ID, DD, epilepsy, and microcephaly.”

• cites [95] Srivastava, S. et al. Expansion of the genotypic and phenotypic spectrum of WASF1-related neurodevelopmental disorder. Brain Sci. 11, https://doi.org/10.3390/brainsci11070931 (2021). sourcePartly supported

  Results §3.1 identifies one patient (P6) with WASF1 c.481T>A (p.W161R); §§3.2–3.3 report developmental impairment in the cohort and infantile spasms in P6. The paper does not report a second p.W161R patient with c.481T>C or compare two such patients, and the retrieved clinical passages do not establish microcephaly. Page numbers were not supplied in our copy. (LLM, conf=0.89)

  Experimental — accuracy not yet measured
• cites [102] Zhao, A. et al. Trio exome sequencing identified a novel de novo WASF1 missense variant leading to recurrent site substitution in a Chinese patient with developmental delay, microcephaly, and early-onset seizures: a mutational hotspot p.Trp161 and literature review. Clin. Chim. Acta 523, 10–18 (2021). sourceNot checked — no full text of the source

Among two nonsense variants and one frameshift variant, the recurrent variant p.Arg506Ter has been identified in three individuals.

“Among two nonsense variants and one frameshift variant, the recurrent variant p.Arg506Ter has been identified in three individuals94–97.”

• cites [94] Shimojima Yamamoto, K. et al. Recurrent de novo pathogenic variant of WASF1 in a Japanese patient with neurodevelopmental disorder with absent language and variable seizures. Hum. Genome Var. 8, 43 (2021). sourcePartly supported

  The paper lists two nonsense variants and one frameshift variant, and says three patients in the earlier report had p.Arg506* (p.Arg506Ter). But its Abstract also identifies that variant in the present patient, bringing the total reported in this paper to four. The unqualified count of three is therefore supported only for the earlier report. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [95] Srivastava, S. et al. Expansion of the genotypic and phenotypic spectrum of WASF1-related neurodevelopmental disorder. Brain Sci. 11, https://doi.org/10.3390/brainsci11070931 (2021). sourceSupported
• cites [96] Tang, X., Liu, G., Lin, L., Xiao, N. & Chen, Y. The recurrent WASF1 nonsense variant identified in two unaffected Chinese families with neurodevelopmental disorder: case report and review of the literatures. BMC Med. Genomics 16, 203 (2023). sourceSupported
• cites [97] van der Sanden, B. et al. The performance of genome sequencing as a first-tier test for neurodevelopmental disorders. Eur. J. Hum. Genet. 31, 81–88 (2023). sourcePartly supported

  Table 2 in Results (SOC diagnostic yield; page unavailable) lists a de novo WASF1 p.(Arg506*) variant in one individual, supporting identification of the nonsense variant. It does not report that variant in three individuals or establish the claimed set of two nonsense variants and one frameshift variant. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

West syndrome was diagnosed in two individuals with CYFIP2 variants, similar to the reported patient with a CYFIP1 variant.

“Interestingly, West syndrome was diagnosed in two individuals118, similar to the reported patient with a CYFIP1 variant116.”

• cites [118] Nakashima, M. et al. De novo hotspot variants in CYFIP2 cause early-onset epileptic encephalopathy. Ann. Neurol. 83, 794–806 (2018). sourceNot checked — no full text of the source
• cites [116] Peng, J. et al. Novel West syndrome candidate genes in a Chinese cohort. CNS Neurosci. Ther. 24, 1196–1206 (2018). sourcePartly supported

  Table 1 lists a CYFIP2 variant in one West syndrome patient (WS1), not two. It also lists a CYFIP1 variant in a separate patient (WS46), but the citing sentence attaches a different citation to that comparison. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

A rare heterozygous disruptive nonsense variant p.Arg624Ter in CYFIP1 was detected in a patient diagnosed with schizophrenia.

“Additionally, a polygenic pattern including a rare heterozygous disruptive nonsense variant, p.Arg624Ter, in CYFIP1 was detected in a patient diagnosed with SCZ115 (Table 2n).”

• cites [115] Purcell, S. M. et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature 506, 185–190 (2014). sourcePartly supported

  Extended Data Tables 3 and 8 report one singleton disruptive CYFIP1 variant in a schizophrenia case and none in controls. The passages do not identify it as p.Arg624Ter or establish that it was a heterozygous nonsense variant. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites Table 2nNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

An intragenic heterozygous deletion covering exons 4-11 of WASF1 was found in an individual with a neurodevelopmental psychiatric disorder.

“An intragenic heterozygous deletion covering exons 4–11 of WASF1 was found in an individual with a neurodevelopmental psychiatric disorder101 (Table 2c).”

• cites [101] Shimelis, H. et al. Prevalence and penetrance of rare pathogenic variants in neurodevelopmental psychiatric genes in a health care system population. Am. J. Psychiatry 180, 65–72 (2023). sourceCould not verify

  The Results section, “Prevalence of NPD-Related Single-Gene Variants” (page unavailable), reports pathogenic variants and a deletion in ASXL3, but does not identify a WASF1 deletion. Searches for WASF1, an intragenic heterozygous deletion, and exons 4–11 found no passage in our copy documenting the claimed individual or variant. (LLM, conf=0.73)

  Experimental — accuracy not yet measured

Drosophila WAVE, Scar, and ARP2/3-dependent nuclear actin polymerization and myosin are also critical for heterochromatin repair and stability.

“Drosophila WAVE, Scar, and ARP2/3-dependent nuclear actin polymerization and myosin are also critical for heterochromatin repair and stability87.”

• cites [87] Caridi, C. P. et al. Nuclear F-actin and myosins drive relocalization of heterochromatic breaks. Nature 559, 54–60 (2018). sourcePartly supported

  The ‘Actin nucleators mediate relocalization of heterochromatic DSBs’ section identifies Wash and Scar as Arp2/3 activators in fly cells, but does not identify WAVE as a separate factor. ‘Nuclear F-actin and myosins promote heterochromatin integrity’ concludes that Arp2/3-dependent nuclear actin polymerization and myosins are critical for heterochromatin repair and stability in Drosophila. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

The WASF1 variant p.Trp161Cys was reported in a patient with intellectual disability, autism, hypotonia, and epilepsy.

“Additionally, the variant p.Trp161Cys was reported in a patient with ID, autism, hypotonia, and epilepsy, whereas p.Lys172Glu was found in a patient with DD, hypotonia, and autism95.”

• cites [95] Srivastava, S. et al. Expansion of the genotypic and phenotypic spectrum of WASF1-related neurodevelopmental disorder. Brain Sci. 11, https://doi.org/10.3390/brainsci11070931 (2021). sourceSupported

A heterozygous deletion due to a CNV spanning exons 8-10 of WASF1 and encompassing the entire GPR6 gene was identified in monozygotic twins with ID, autism, and epilepsy.

“A heterozygous deletion due to a CNV spanning exons 8–10 of WASF1 and encompassing the entire GPR6 gene was identified in monozygotic twins with ID, autism, and epilepsy95 (Table 2b).”

• cites [95] Srivastava, S. et al. Expansion of the genotypic and phenotypic spectrum of WASF1-related neurodevelopmental disorder. Brain Sci. 11, https://doi.org/10.3390/brainsci11070931 (2021). sourcePartly supported

  Results §3.1 identifies a deletion of WASF1 exons 8–10 and the entire GPR6 gene in monozygotic twin sisters; the reported single copy supports its description as heterozygous. Results §§3.2–3.3 support ID and epilepsy in the twins, but §3.2 describes autism as nearly universal in the cohort without identifying whether both twins had it. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

When double strands of DNA break, nuclear F-actin is required for the non-homologous end joining and homologous recombination repair pathways.

“In contrast, when double strands of DNA break, nuclear F-actin is required for the non-homologous end joining and homologous recombination repair pathways92.”

• cites [92] Caridi, C. P., Plessner, M., Grosse, R. & Chiolo, I. Nuclear actin filaments in DNA repair dynamics. Nat. Cell Biol. 21, 1068–1077 (2019). sourcePartly supported

  The section “Nuclear F-actin is required for DSB repair” identifies NHEJ and HR as the two major DSB repair pathways and reports that components of both bind F-actin. It also reports defective repair when nuclear actin polymerization is inhibited, but describes F-actin’s direct roles as suggested and enigmatic; it does not establish that F-actin is required for each pathway individually. No page number is available in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

These CYFIP1 mutations occur in protein domains responsible for maintaining interactions within the WAVE complex.

“These mutations occur in protein domains responsible for maintaining interactions within the WAVE complex.”

• cites [111] Mariano, V. et al. Intellectual disability and behavioral deficits linked to CYFIP1 missense variants disrupting actin polymerization. Biol. Psychiatry 95, 161–174 (2024). sourceSupported

A homozygous loss-of-function mutation p.Arg132Ter in ABI2 was identified in a cohort of 192 multiplex Pakistani and Iranian consanguineous families.

“Furthermore, a homozygous LoF mutation, p.Arg132Ter, in ABI2 was identified through a combination of microarray genotyping, homozygosity-by-descent (HBD) mapping, CNV analysis, and exome sequencing. This discovery was made within a cohort of 192 multiplex Pakistani and Iranian consanguineous families.”

• cites [140] Harripaul, R. et al. Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families. Mol. Psychiatry 23, 973–984 (2018). sourceSupported

Reduced WAVE1 expression has a protective role in Alzheimer's disease.

“WAVE1 KO dramatically reduces Aβ levels and restores memory deficits in APP/PS1 transgenic mice expressing familial mutations in APP (APPswe) and presenilin 1 (PSEN1 ΔE9)146, suggesting a protective role for reduced WAVE1 expression in AD143.”

• cites [143] Ceglia, I. et al. APP intracellular domain-WAVE1 pathway reduces amyloid-beta production. Nat. Med. 21, 1054–1059 (2015). sourceSupported

ABI2 is one of 26 newly identified candidate genes associated with autosomal recessive non-syndromic intellectual disability.

“ABI2 is one of the 26 newly identified candidate genes associated with autosomal recessive non-syndromic ID140 (Table 2x).”

• cites [140] Harripaul, R. et al. Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families. Mol. Psychiatry 23, 973–984 (2018). sourceSupported
• cites Table 2xNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Abi1-null mouse embryos exhibited lethality between E10.5 and E11.5.

“Abi1-null mouse embryos exhibited lethality between E10.5 and E11.5139.”

• cites [139] Dubielecka, P. M. et al. Essential role for Abi1 in embryonic survival and WAVE2 complex integrity. Proc. Natl Acad. Sci. USA 108, 7022–7027 (2011). sourceSupported

An analysis of genome sequencing data from 2,308 individuals in 493 multiplex ASD families from the Autism Genetic Resource Exchange conducted through TADA mega-analysis identified NCKAP1 among 69 genes associated with an ASD risk.

“An analysis of genome sequencing data from 2,308 individuals in 493 multiplex ASD families from the Autism Genetic Resource Exchange (AGRE) conducted through TADA (Transmitted And De novo Association) mega-analysis identified NCKAP1 among 69 genes associated with an ASD risk128.”

• cites [128] Ruzzo, E. K. et al. Inherited and de novo genetic risk for autism impacts shared networks. Cell 178, 850–866.e826 (2019). sourcePartly supported

  The Results section reports whole-genome sequencing of 2,308 individuals in 493 AGRE multiplex ASD families and identifies 69 ASD-associated genes in a TADA mega-analysis. Our copy does not identify NCKAP1 as one of those genes. The Methods also clarify that the mega-analysis combined the AGRE cohort’s variants with data from other cohorts, rather than analyzing only the 2,308 individuals. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Abi1-KO cells displayed defective regulation of the actin cytoskeleton, which was attributed to altered activity of the WAVE1 and 2 complexes.

“Abi1-KO cells displayed defective regulation of the actin cytoskeleton, which was attributed to altered activity of the WAVE1 and 2 complexes.”

• cites [139] Dubielecka, P. M. et al. Essential role for Abi1 in embryonic survival and WAVE2 complex integrity. Proc. Natl Acad. Sci. USA 108, 7022–7027 (2011). sourcePartly supported

  The paper’s opening summary attributes defective actin-cytoskeleton regulation in Abi1-KO cells to altered activity of the WAVE2 complex. The Results section also reports reduced WAVE1 protein levels, but the passages do not attribute the defect to altered activity of a distinct WAVE1 complex. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

In some Abi1-null embryos, the neural tube was open.

“In some embryos, the neural tube was open.”

• cites [139] Dubielecka, P. M. et al. Essential role for Abi1 in embryonic survival and WAVE2 complex integrity. Proc. Natl Acad. Sci. USA 108, 7022–7027 (2011). sourceSupported

A nonsense variant (p.Glu1100Ter) of NCKAP1 was identified as segregating within a multi-generational family comprising 13 affected members exhibiting mild intellectual disability, ADHD, macrocephaly, and tall stature.

“A nonsense variant (p.Glu1100Ter) of NCKAP1 was identified as segregating within a multi-generational family comprising 13 affected members exhibiting mild ID, ADHD, macrocephaly, and tall stature (Table 2s).”

• cites [126] Anazi, S. et al. Expanding the genetic heterogeneity of intellectual disability. Hum. Genet. 136, 1419–1429 (2017). sourcePartly supported

  The Identification of Novel Candidate ID Genes section describes a large multigenerational family with mild intellectual disability and a heterozygous truncating NCKAP1 variant. The table in the Figure Legends identifies p.(Glu1100*) and lists ADHD, but the passages do not substantiate 13 affected members, macrocephaly, or tall stature. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Table 2sNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Next-generation sequencing identified one intronic, two missense, and two nonsense variants in NCKAP1L in autism patients.

“Next-generation sequencing identified one intronic114, two missense133,134, and two nonsense variants in autism patients104,114, and the functional consequences of these variants remain to be established (Table 2u).”

• cites [114] Fu, J. M. et al. Rare coding variation provides insight into the genetic architecture and phenotypic context of autism. Nat. Genet. 54, 1320–1331 (2022). sourceCould not verify

  The Results section reports exome sequencing and protein-truncating and missense variants in ASD cohorts, but it does not identify NCKAP1L or give the claimed variant counts. Searches for NCKAP1L and for the intronic, missense, and nonsense variant combination found no passage in our copy establishing the NCKAP1L variants attributed to this source. (LLM, conf=0.72)

  Experimental — accuracy not yet measured
• cites [133] Iossifov, I. et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature 515, 216–221 (2014). sourceCould not verify

  The Results section describes exome sequencing in children with autism, but the passages retrieved for “NCKAP1L” and “intronic variants in NCKAP1L autism” do not identify that gene or give the claimed variant counts. Our copy therefore does not establish whether this study found an intronic, missense, or nonsense NCKAP1L variant. (LLM, conf=0.72)

  Experimental — accuracy not yet measured
• cites [134] Krupp, D. R. et al. Exonic mosaic mutations contribute risk for autism spectrum disorder. Am. J. Hum. Genet. 101, 369–390 (2017). sourceNot checked — no full text of the source

Two de novo heterozygous missense mutations in ABI2, p.Arg373Cys and p.Glu202Lys, were identified in two ASD probands from two independent simplex quad families through exome sequencing data from the Simons Simplex Collection.

“Two de novo heterozygous missense mutations, ABI2-p.Arg373Cys and p.Glu202Lys, were identified in two ASD probands from two independent simplex quad families through exome sequencing data retrieved from the Simons Simplex Collection (SSC)127 (Table 2w).”

• cites [127] Guo, H. et al. Genome-wide copy number variation analysis in a Chinese autism spectrum disorder cohort. Sci. Rep. 7, 44155 (2017). sourcePartly supported

  The Discussion (page unavailable) reports two de novo ABI2 missense mutations in two ASD probands from simplex quad families, identified by analyzing SSC and ASC whole-exome data. Our copy does not name the variants p.Arg373Cys and p.Glu202Lys or specify that they were heterozygous, so those details cannot be verified from it. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites Table 2wNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

These disruptions are accompanied by severe deficits in both short- and long-term memory.

“These disruptions are accompanied by severe deficits in both short- and long-term memory141.”

• cites [141] Grove, M. et al. ABI2-deficient mice exhibit defective cell migration, aberrant dendritic spine morphogenesis, and deficits in learning and memory. Mol. Cell Biol. 24, 10905–10922 (2004). sourceSupported

The WAVE1 gene has been suggested as an AD-associated hub gene from studies of AD mouse models or human AD brains.

“The WAVE1 gene has also been suggested as an AD-associated hub gene from studies of AD mouse models148 or human AD brains149.”

• cites [148] Savas, J. N. et al. Amyloid accumulation drives proteome-wide alterations in mouse models of Alzheimer’s disease-like pathology. Cell Rep. 21, 2614–2627 (2017). sourceSupported
• cites [149] Zhang, Q. et al. Integrated proteomics and network analysis identifies protein hubs and network alterations in Alzheimer’s disease. Acta Neuropathol. Commun. 6, 19 (2018). sourcePartly supported

  In the Results section on AD-associated network modules (page not provided), the paper lists WASF1 (WAVE1) among proteins in an AD-associated module from human brain samples. It identifies other proteins—not WASF1—as that module’s top hubs, so it does not establish WAVE1 as a hub gene. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

The phenotype in the heterozygous Cyfip2 knockout mouse model was milder than the severe phenotype observed in humans heterozygous for CYFIP2 variants.

“However, the phenotype in the heterozygous Cyfip2 KO mouse model was milder than the severe phenotype observed in humans heterozygous for variants121.”

• cites [121] Zweier, M. et al. Spatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein 2, cause intellectual disability and seizures. Eur. J. Hum. Genet. 27, 747–759 (2019). sourceSupported

Two de novo truncating mutations in NCKAP1 (p.Gly175TrpfsTer14 and p.Glu1088Ter) were identified in two ASD probands from two unrelated simplex quad families.

“In the Simons Simplex Collection (SSC), two de novo truncating mutations in NCKAP1-p.Gly175TrpfsTer14 and p.Glu1088Ter- were identified in two ASD probands from two unrelated simplex quad families127.”

• cites [127] Guo, H. et al. Genome-wide copy number variation analysis in a Chinese autism spectrum disorder cohort. Sci. Rep. 7, 44155 (2017). sourcePartly supported

  The Discussion (page unavailable) reports recurrent de novo likely gene-disruptive NCKAP1 mutations in ASD patients. It does not give the two variant names or establish that the NCKAP1 mutations occurred in probands from two unrelated SSC simplex quad families; the nearby statement about two such probands concerns ABI2 mutations instead. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

The colocalization of WAVE1 protein or phosphorylated WAVE1 with aggregated hyperphosphorylated tau was observed in the brains of triple transgenic mice and human AD patients.

“The colocalization of the WAVE1 protein or phosphorylated WAVE1 with aggregated hyperphosphorylated tau was observed in the brains of triple transgenic mice (APPswe/PS1M146V/tauP301L)47 and human AD patients147.”

• cites [47] Watamura, N., Toba, J., Yoshii, A., Nikkuni, M. & Ohshima, T. Colocalization of phosphorylated forms of WAVE1, CRMP2, and tau in Alzheimer’s disease model mice: involvement of Cdk5 phosphorylation and the effect of ATRA treatment. J. Neurosci. Res. 94, 15–26 (2016). sourceNot checked — no full text of the source
• cites [147] Takata, K. et al. Involvement of WAVE accumulation in Abeta/APP pathology-dependent tangle modification in Alzheimer’s disease. Am. J. Pathol. 175, 17–24 (2009). sourceSupported

The homozygous deletion of murine Abi2 led to abnormal phenotypes in the eye and brain, which are the tissues with the highest ABI2 expression.

“The homozygous deletion of murine Abi2 led to abnormal phenotypes in the eye and brain, which are the tissues with the highest ABI2 expression.”

• cites [141] Grove, M. et al. ABI2-deficient mice exhibit defective cell migration, aberrant dendritic spine morphogenesis, and deficits in learning and memory. Mol. Cell Biol. 24, 10905–10922 (2004). sourceSupported

Pathogenic variants within the same neurodevelopmental gene may result in diverse clinical presentations, including differences in severity.

“Additionally, pathogenic variants within the same neurodevelopmental gene may result in diverse clinical presentations, including differences in severity125.”

• cites [125] Jansen, S., Vissers, L. & de Vries, B. B. A. The genetics of intellectual disability. Brain Sci. 13, https://doi.org/10.3390/brainsci13020231 (2023). sourcePartly supported

  The Introduction (page unavailable) says that mutations in the same gene can cause clinical variability within an intellectual-disability disorder. It does not specifically link that variability to differences in severity, and its statement concerns intellectual disability rather than neurodevelopmental disorders generally. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

This NCKAP1 variant is expressed in cells in diverse brain regions, including Purkinje cells, the dentate nucleus of the cerebellum, the CA4 region, the dentate gyrus of the hippocampus, and frontal gray and white matter regions.

“This variant is expressed in cells in diverse brain regions, including Purkinje cells, the dentate nucleus of the cerebellum, the CA4 region, and the dentate gyrus of the hippocampus, and frontal gray and white matter regions126.”

• cites [126] Anazi, S. et al. Expanding the genetic heterogeneity of intellectual disability. Hum. Genet. 136, 1419–1429 (2017). sourcePartly supported

  The Identification of Novel Candidate ID Genes section and Figure 4 legend report NCKAP1 protein in all the listed regions of normal adult human brain. The study did not show that the particular NCKAP1 variant is expressed in those cells; its expression analysis concerned NCKAP1 protein generally. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Three individuals harboring loss-of-function CYFIP2 variants (p.Lys501Ter, p.Ser258Glnfs2, and c.2058-1G > C) exhibited clinical features such as developmental delay, intellectual disability, ADHD, behavioral problems, seizures, craniofacial anomalies, and digital anomalies.

“Among them, three individuals harboring LoF variants—p.Lys501Ter, p.Ser258Glnfs2, and c.2058-1G > C—exhibited clinical features such as DD, ID, attention-deficit/hyperactivity disorder (ADHD), behavioral problems, seizures, craniofacial anomalies, and digital anomalies.”

• cites [124] Begemann, A. et al. New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics. Genet. Med. 23, 543–554 (2021). sourcePartly supported

  The Results section (‘No evidence that loss-of-function variants lead to a similarly severe phenotype’; page unavailable) identifies the three variants and reports mild intellectual disability and epilepsy in individual 19, and language delay and behavioral problems in individuals 17 and 18. It does not report ADHD, craniofacial anomalies, or digital anomalies for these three individuals; the facial features and tapered fingers described elsewhere in Results concern individuals with likely disease-associated missense variants. The authors also say the clinical significance of the three putative loss-of-function variants remains unclear. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

A total of eight distinct de novo variants in CYFIP2 were identified among 12 independent patients who shared a phenotype characterized by intellectual disability, seizures, and muscular hypotonia.

“Using trio next-generation sequencing, a total of eight distinct de novo variants in CYFIP2 were identified among 12 independent patients who shared a phenotype characterized by ID, seizures, and muscular hypotonia.”

• cites [121] Zweier, M. et al. Spatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein 2, cause intellectual disability and seizures. Eur. J. Hum. Genet. 27, 747–759 (2019). sourceSupported

A likely mechanism supported by experimental data is that AICD generated from the amyloidogenic pathway binds to the WAVE1 promoter and negatively regulates its transcription and protein expression.

“A likely mechanism supported by the experimental data is that the AICD (APP intracellular domain) generated from the amyloidogenic pathway binds to the WAVE1 promoter and negatively regulates its transcription and protein expression143.”

• cites [143] Ceglia, I. et al. APP intracellular domain-WAVE1 pathway reduces amyloid-beta production. Nat. Med. 21, 1054–1059 (2015). sourceSupported

A nonsense variant c.367C > T (p.Arg213Ter) in ABI1 was identified in a patient with cardiovascular dysfunction and neurodevelopmental disorder.

“A nonsense variant, c.367C > T, p.Arg213Ter, in ABI1 was identified in a patient with cardiovascular dysfunction and NDD135–137 (Table 2v).”

• cites [135] Edwards, J. J. et al. Systems analysis implicates WAVE2 complex in the pathogenesis of developmental left-sided obstructive heart defects. JACC Basic Transl. Sci. 5, 376–386 (2020). sourcePartly supported

  The Results (Gene set enrichment analyses; page unavailable) identify a nonsense ABI1 variant in a proband with a left-sided obstructive heart defect, but report it as p.R106X, not p.Arg213Ter. Our copy does not identify c.367C>T or say that this proband had a neurodevelopmental disorder. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [136] Jin, S. C. et al. Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. Nat. Genet. 49, 1593–1601 (2017). sourceCould not verify

  The Results section on de novo mutations in autism-associated genes reports an overlap between congenital heart disease and neurodevelopmental disorders, but does not identify the patient or ABI1 variant in the claim. Searches for ABI1, c.367C>T, and p.Arg213Ter found no passage in our copy documenting that specific case; page numbers were not provided. (LLM, conf=0.72)

  Experimental — accuracy not yet measured
• cites [137] Morton, S. U. et al. Association of damaging variants in genes with increased cancer risk among patients with congenital heart disease. JAMA Cardiol. 6, 457–462, (2021). sourceCould not verify

  The Results sections on candidate congenital-heart-disease genes and comorbid neurodevelopmental defects discuss loss-of-function variants in other genes, but do not identify an ABI1 variant or the patient described. Searches of our copy for “ABI1,” “c.367C > T,” and “Arg213Ter” found no matching passage. The cited paper therefore does not verify this specific case in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites Table 2vNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Downregulation of WASF1 expression in the AD brain has also been observed in publicly available datasets.

“Downregulation of WASF1 expression in the AD brain has also been observed in publicly available datasets144,145.”

• cites [144] Webster, J. A. et al. Genetic control of human brain transcript expression in Alzheimer disease. Am. J. Hum. Genet. 84, 445–458 (2009). sourceCould not verify

  The Discussion (page unavailable) says the study’s brain-expression data were deposited publicly as GEO GSE15222. However, the passages from our copy do not report WASF1 expression or its direction of change in Alzheimer disease; searches for WASF1, WAVE1, and reduced expression did not establish the claimed downregulation. (LLM, conf=0.72)

  Experimental — accuracy not yet measured
• cites [145] Hill, M. A. & Gammie, S. C. Alzheimer’s disease large-scale gene expression portrait identifies exercise as the top theoretical treatment. Sci. Rep. 12, 17189 (2022). sourceCould not verify

  The Methods section describes publicly available AD brain-expression datasets, but the passages in our copy do not report whether WASF1 is downregulated. Searches for WASF1, WAVE1, and its full gene name found no passage addressing that specific result. (LLM, conf=0.74)

  Experimental — accuracy not yet measured

WAVE2 and its phosphorylation are involved in LRRK2-G2019S-induced dopaminergic neuronal death in macrophage and midbrain cocultures.

“In addition, WAVE2 and its phosphorylation are involved in LRRK2-G2019S-induced dopaminergic neuronal death in macrophage and midbrain cocultures.”

• cites [169] Kim, K. S. et al. Regulation of myeloid cell phagocytosis by LRRK2 via WAVE2 complex stabilization is altered in Parkinson’s disease. Proc. Natl Acad. Sci. USA 115, E5164–E5173 (2018). sourceSupported

Deletion of the Cyfip2 allele in C57BL/6N mice results in acute and sensitized cocaine response phenotypes.

“CYFIP2 is destabilized by the Ser968Phe mutation, and deletion of the allele in C57BL/6N mice results in acute and sensitized cocaine response phenotypes, suggesting that CYFIP2 is a critical regulator of the cocaine response171.”

• cites [171] Kumar, V. et al. C57BL/6N mutation in cytoplasmic FMRP interacting protein 2 regulates cocaine response. Science 342, 1508–1512 (2013). sourceSupported

Abi3-Gngt2 dual knockout predisposes mice to an immune phenotype characterized by reactive gliosis and gene expression patterns resembling those associated with AD.

“Abi3-Gngt2 dual KO predisposes mice to an immune phenotype characterized by reactive gliosis and gene expression patterns resembling those associated with AD.”

• cites [53] Ibanez, K. R. et al. Deletion of Abi3/Gngt2 influences age-progressive amyloid beta and tau pathologies in distinctive ways. Alzheimers Res. Ther. 14, 104 (2022). sourceSupported

WAVE1 deletion in neurons expressing the dopamine D1 receptor but not the dopamine D2 receptor significantly decreases cocaine reward, as measured by cocaine-associated place preference and cocaine-induced sensitized locomotor behavior.

“WAVE1 deletion in neurons expressing the dopamine D1 receptor but not the dopamine D2 receptor significantly decreases cocaine reward, as measured by cocaine-associated place preference and cocaine-induced sensitized locomotor behavior11.”

• cites [11] Ceglia, I. et al. WAVE1 in neurons expressing the D1 dopamine receptor regulates cellular and behavioral actions of cocaine. Proc. Natl Acad. Sci. USA 114, 1395–1400 (2017). sourcePartly supported

  The Results report significantly reduced cocaine-conditioned place preference in WAVE1 D1-KO mice, but not D2-KO mice. They also report that both knockout groups developed locomotor sensitization; only D1-KO mice showed a lower response to a cocaine challenge after withdrawal. The claim omits that qualification and treats locomotor sensitization as a measure of reward. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

WAVE2 levels are also reduced in primary microglia and bone marrow-derived macrophages from LRRK2 knockout mice.

“WAVE2 levels are also reduced in primary microglia and bone marrow-derived macrophages from LRRK2 KO mice.”

• cites [169] Kim, K. S. et al. Regulation of myeloid cell phagocytosis by LRRK2 via WAVE2 complex stabilization is altered in Parkinson’s disease. Proc. Natl Acad. Sci. USA 115, E5164–E5173 (2018). sourceSupported

Cocaine administration also reduces inhibitory phosphorylation at Ser310, 397 and 441 on WAVE1 in an NMDA receptor- or dopamine D1 receptor-dependent manner.

“Cocaine administration also reduces inhibitory phosphorylation at Ser310, 397 and 441 on WAVE1 in an NMDA receptor- or dopamine D1 receptor-dependent manner.”

• cites [11] Ceglia, I. et al. WAVE1 in neurons expressing the D1 dopamine receptor regulates cellular and behavioral actions of cocaine. Proc. Natl Acad. Sci. USA 114, 1395–1400 (2017). sourcePartly supported

  The Results report reduced phosphorylation at Ser310, Ser397, and Ser441 after an acute cocaine challenge following chronic cocaine administration and 14 days of withdrawal; D1 or NMDA receptor antagonists largely blocked the effect. The claim omits that essential regimen: the same Results section reports no significant phosphorylation change after acute or chronic cocaine administration alone. Page numbers were not supplied in our copy. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

CYFIP1 is decreased in individuals with late-stage AD.

“CYFIP1 is also decreased in individuals with late-stage AD, but the protein levels of both CYFIP1 and CYFIP2 are increased in the postmortem hippocampal tissues of patients with frontotemporal lobar degeneration (FTLD) with TDP43 pathology154.”

• cites [154] Peng, X., Wellard, N., Ghosh, A., Troakes, C. & Giese, K. P. Different dysregulations of CYFIP1 and CYFIP2 in distinct types of dementia. Brain Res. Bull. 206, 110849 (2024). sourceSupported

Cyfip2 heterozygous knockout mice on a C57BL/6N background presented reduced binge eating comparable to that of wild-type C57BL/6J-like mice.

“Cyfip2 heterozygous KO mice on a C57BL/6N background presented reduced binge eating comparable to that of wild-type C57BL/6J-like mice.”

• cites [177] Kirkpatrick, S. L. et al. Cytoplasmic FMR1-interacting protein 2 is a major genetic factor underlying binge eating. Biol. Psychiatry 81, 757–769 (2017). sourceSupported

Another study of BXD mouse strains suggested that Cyfip2 is a candidate gene associated with different intake responses in a cocaine self-administration paradigm.

“Another study of BXD mouse strains suggested that Cyfip2 is a candidate gene associated with different intake responses in a cocaine self-administration paradigm174.”

• cites [174] Dickson, P. E. et al. Systems genetics of intravenous cocaine self-administration in the BXD recombinant inbred mouse panel. Psychopharmacology 233, 701–714 (2016). sourceSupported

An increase in WAVE2 expression was observed in microglia and macrophages from LRRK2-G2019S knock-in mice.

“However, an increase in WAVE2 expression was observed in microglia and macrophages from LRRK2-G2019S knock-in mice169.”

• cites [169] Kim, K. S. et al. Regulation of myeloid cell phagocytosis by LRRK2 via WAVE2 complex stabilization is altered in Parkinson’s disease. Proc. Natl Acad. Sci. USA 115, E5164–E5173 (2018). sourceSupported

The AD-associated genes Trem2, Plcg2, Tyrobp, and Csf1r are upregulated in a gene dose-dependent manner in these mice, even in the absence of Aβ accumulation.

“Notably, the AD-associated genes Trem2, Plcg2, Tyrobp, and Csf1r are upregulated in a gene dose-dependent manner in these mice, even in the absence of Aβ accumulation.”

• cites [53] Ibanez, K. R. et al. Deletion of Abi3/Gngt2 influences age-progressive amyloid beta and tau pathologies in distinctive ways. Alzheimers Res. Ther. 14, 104 (2022). sourceSupported

Genetic screening of C57BL/6N mice, which have a low acute and sensitized response to psychostimulants compared with C57BL/6J mice, identified a Ser968Phe mutation in Cyfip2 as a causative variant.

“Genetic screening of C57BL/6N mice, which have a low acute and sensitized response to psychostimulants compared with C57BL/6J mice, identified a Ser968Phe mutation in Cyfip2 as a causative variant171.”

• cites [171] Kumar, V. et al. C57BL/6N mutation in cytoplasmic FMRP interacting protein 2 regulates cocaine response. Science 342, 1508–1512 (2013). sourceSupported

Cryo-electron microscopy of the WAVE complex with RAC1 indicated that the Ser968Phe mutation in CYFIP1 (corresponding to Ser968Phe in CYFIP2) is located just beneath the RAC1 binding site.

“Alternatively, cryo-electron microscopy of the WAVE complex with RAC1 indicated that the Ser968Phe mutation in CYFIP1 (corresponding to Ser968Phe in CYFIP2) is located just beneath the RAC1 binding site.”

• cites [172] Chen, B. et al. Rac1 GTPase activates the WAVE regulatory complex through two distinct binding sites. Elife 6, https://doi.org/10.7554/eLife.29795 (2017). sourcePartly supported

  The Results and Discussion place S969F in Sra1 (CYFIP1) immediately beneath the D Site, a Rac1-binding site, and identify S968F in CYFIP2 as the equivalent mutation. The claim gets the location right but gives the CYFIP1 residue as Ser968 rather than the paper’s Ser969. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Human genetics studies of AD identified a coding variant of ABI3, p.Ser209Phe (rs616338), associated with late-onset AD.

“Human genetics studies of AD identified a coding variant of ABI3, p.Ser209Phe (rs616338), associated with late-onset AD158–161 (Table 2y).”

• cites [158] Bellenguez, C. et al. New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat. Genet. 54, 412–436 (2022). sourcePartly supported

  The GWAS meta-analysis (Table 1; page not provided) reports a significant association between rs616338 at the ABI3 locus and Alzheimer’s disease or related dementia. Our copy does not identify rs616338 as the coding substitution p.Ser209Phe, so it does not support that specific characterization. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [159] Conway, O. J. et al. ABI3 and PLCG2 missense variants as risk factors for neurodegenerative diseases in Caucasians and African Americans. Mol. Neurodegener. 13, 53 (2018). sourceSupported
• cites [160] Sims, R. et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat. Genet. 49, 1373–1384 (2017). sourceSupported
• cites [161] Olive, C. et al. Examination of the effect of rare variants in TREM2, ABI3, and PLCG2 in LOAD through multiple phenotypes. J. Alzheimers Dis. 77, 1469–1482 (2020). sourceSupported
• cites Table 2yNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Due to the genetic overlap between Abi3 and Gngt2 on chromosome 11q in mice, Abi3 knockout also targets Gngt2.

“Due to the genetic overlap between Abi3 and Gngt2 on chromosome 11q in mice (not present in humans at 17q21.32 with a reverse transcription direction), Abi3 KO also targets Gngt253.”

• cites [53] Ibanez, K. R. et al. Deletion of Abi3/Gngt2 influences age-progressive amyloid beta and tau pathologies in distinctive ways. Alzheimers Res. Ther. 14, 104 (2022). sourcePartly supported

  The Results section states that mouse Abi3 overlaps Gngt2 on chromosome 11 and that the targeted Abi3 deletion knocked out both genes, supporting the main claim. It does not specify chromosome arm 11q. The citing sentence’s parenthetical is also at odds with the Results, which say the gene arrangement is conserved in humans on chromosome 17. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

WAVE1 is required in neurons expressing the dopamine D1 receptor for cocaine-evoked glutamatergic synaptic plasticity.

“WAVE1 is required in neurons expressing the dopamine D1 receptor for cocaine-evoked glutamatergic synaptic plasticity11.”

• cites [11] Ceglia, I. et al. WAVE1 in neurons expressing the D1 dopamine receptor regulates cellular and behavioral actions of cocaine. Proc. Natl Acad. Sci. USA 114, 1395–1400 (2017). sourceSupported

CYFIP2 was also identified as a significant genetic factor underlying binge eating by analyzing closely related C57BL/6 mouse substrains.

“CYFIP2 was also identified as a significant genetic factor underlying binge eating by analyzing closely related C57BL/6 mouse substrains177.”

• cites [177] Kirkpatrick, S. L. et al. Cytoplasmic FMR1-interacting protein 2 is a major genetic factor underlying binge eating. Biol. Psychiatry 81, 757–769 (2017). sourceSupported

This alteration could be interpreted as causing hypomorphic function or partial loss-of-function of ABI3.

“This alteration could be interpreted as causing hypomorphic function or partial LoF53.”

• cites [53] Ibanez, K. R. et al. Deletion of Abi3/Gngt2 influences age-progressive amyloid beta and tau pathologies in distinctive ways. Alzheimers Res. Ther. 14, 104 (2022). sourceSupported

CYFIP2 is a critical regulator of the cocaine response.

“CYFIP2 is destabilized by the Ser968Phe mutation, and deletion of the allele in C57BL/6N mice results in acute and sensitized cocaine response phenotypes, suggesting that CYFIP2 is a critical regulator of the cocaine response171.”

• cites [171] Kumar, V. et al. C57BL/6N mutation in cytoplasmic FMRP interacting protein 2 regulates cocaine response. Science 342, 1508–1512 (2013). sourceSupported

WAVE1 is also required for cocaine-induced behavioral and synaptic plasticity.

“WAVE1 is also required for cocaine-induced behavioral and synaptic plasticity11.”

• cites [11] Ceglia, I. et al. WAVE1 in neurons expressing the D1 dopamine receptor regulates cellular and behavioral actions of cocaine. Proc. Natl Acad. Sci. USA 114, 1395–1400 (2017). sourcePartly supported

  The Discussion reports that deleting WAVE1 in D1-expressing neurons reduced cocaine place preference and maintenance of locomotor sensitization, while the Results and Discussion describe WAVE1-dependent spine and AMPA-current changes after a cocaine challenge following chronic exposure and withdrawal. But the Discussion also says WAVE1 was not required for the development of locomotor sensitization or the spine-density increase after chronic cocaine exposure. The unqualified claim is therefore broader than the findings. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

ABI3 is highly expressed in microglia.

“ABI3 is highly expressed in microglia162,163 (Fig. 1c and Table 1), and ABI3 expression is increased in postmortem AD brains162,164.”

• cites [162] Turner, A. K., Shaw, B. C., Simpson, J. F. & Estus, S. Identification and quantitation of novel ABI3 isoforms relative to Alzheimer’s disease genetics and neuropathology. Genes 13, https://doi.org/10.3390/genes13091607 (2022). sourceSupported
• cites [163] Satoh, J. I. et al. Microglia express ABI3 in the brains of Alzheimer’s disease and Nasu-Hakola disease. Intractable Rare Dis. Res. 6, 262–268 (2017). sourceSupported
• cites Fig. 1cNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

C57BL/6N mice, but not C57BL/6J mice, showed rapid and robust escalation in palatable food consumption.

“C57BL/6N mice, but not C57BL/6J mice, showed rapid and robust escalation in palatable food consumption.”

• cites [177] Kirkpatrick, S. L. et al. Cytoplasmic FMR1-interacting protein 2 is a major genetic factor underlying binge eating. Biol. Psychiatry 81, 757–769 (2017). sourceSupported

In BV2 microglia, LRRK2 knockdown reduces the level of WAVE2 but not the levels of WAVE1 and WAVE3.

“In BV2 microglia, LRRK2 knockdown reduces the level of WAVE2 but not the levels of WAVE1 and WAVE3.”

• cites [169] Kim, K. S. et al. Regulation of myeloid cell phagocytosis by LRRK2 via WAVE2 complex stabilization is altered in Parkinson’s disease. Proc. Natl Acad. Sci. USA 115, E5164–E5173 (2018). sourceSupported

C57BL/6 mouse substrains have different locomotor activities and sensitized responses to cocaine and methamphetamine.

“C57BL/6 mouse substrains have different locomotor activities and sensitized responses to cocaine and methamphetamine.”

• cites [171] Kumar, V. et al. C57BL/6N mutation in cytoplasmic FMRP interacting protein 2 regulates cocaine response. Science 342, 1508–1512 (2013). sourceSupported

The protein levels of both CYFIP1 and CYFIP2 are increased in the postmortem hippocampal tissues of patients with frontotemporal lobar degeneration with TDP43 pathology.

“CYFIP1 is also decreased in individuals with late-stage AD, but the protein levels of both CYFIP1 and CYFIP2 are increased in the postmortem hippocampal tissues of patients with frontotemporal lobar degeneration (FTLD) with TDP43 pathology154.”

• cites [154] Peng, X., Wellard, N., Ghosh, A., Troakes, C. & Giese, K. P. Different dysregulations of CYFIP1 and CYFIP2 in distinct types of dementia. Brain Res. Bull. 206, 110849 (2024). sourceSupported

ABI3 expression is increased in postmortem AD brains.

“ABI3 is highly expressed in microglia162,163 (Fig. 1c and Table 1), and ABI3 expression is increased in postmortem AD brains162,164.”

• cites [162] Turner, A. K., Shaw, B. C., Simpson, J. F. & Estus, S. Identification and quantitation of novel ABI3 isoforms relative to Alzheimer’s disease genetics and neuropathology. Genes 13, https://doi.org/10.3390/genes13091607 (2022). sourceSupported
• cites [164] Karahan, H. et al. Deletion of Abi3 gene locus exacerbates neuropathological features of Alzheimer’s disease in a mouse model of Abeta amyloidosis. Sci. Adv. 7, eabe3954 (2021). sourceSupported

CYFIP2 is destabilized by the Ser968Phe mutation.

“CYFIP2 is destabilized by the Ser968Phe mutation, and deletion of the allele in C57BL/6N mice results in acute and sensitized cocaine response phenotypes, suggesting that CYFIP2 is a critical regulator of the cocaine response171.”

• cites [171] Kumar, V. et al. C57BL/6N mutation in cytoplasmic FMRP interacting protein 2 regulates cocaine response. Science 342, 1508–1512 (2013). sourceSupported

Several studies have used intact WAVE complexes isolated from the brain or cells.

“In fact, several studies have used intact WAVE complexes isolated from the brain or cells19,20,22,179.”

• cites [19] Eden, S., Rohatgi, R., Podtelejnikov, A. V., Mann, M. & Kirschner, M. W. Mechanism of regulation of WAVE1-induced actin nucleation by Rac1 and Nck. Nature 418, 790–793 (2002). sourceNot checked — no full text of the source
• cites [20] Lebensohn, A. M. & Kirschner, M. W. Activation of the WAVE complex by coincident signals controls actin assembly. Mol. Cell 36, 512–524 (2009). sourceSupported
• cites [22] Kim, Y. et al. Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology. Nature 442, 814–817 (2006). sourceNot checked — no full text of the source

The native full-length WAVE2 complex was successfully activated by the cooperative actions of prenylated RAC-GTP, acidic phospholipids and phosphorylation.

“The native full-length WAVE2 complex was successfully activated by the cooperative actions of prenylated RAC-GTP, acidic phospholipids and phosphorylation20.”

• cites [20] Lebensohn, A. M. & Kirschner, M. W. Activation of the WAVE complex by coincident signals controls actin assembly. Mol. Cell 36, 512–524 (2009). sourceSupported

Structural studies of the WAVE complex in vitro have used a recombinant WAVE complex containing mini-WAVE, which lacks the proline-rich region due to the disordered nature of this region and difficulty in crystallization.

“Structural studies of the WAVE complex in vitro have used a recombinant WAVE complex containing mini-WAVE21,28,30,172, which lacks the proline-rich region due to the disordered nature of this region and difficulty in crystallization21.”

• cites [21] Chen, Z. et al. Structure and control of the actin regulatory WAVE complex. Nature 468, 533–538 (2010). sourcePartly supported

  In “Overall structure of the WRC” (page unavailable), the paper says it replaced WAVE1’s proline-rich region with a linker and removed Abi2’s proline-rich region to facilitate crystallization of the miniWRC. The passage does not say that disorder in the proline-rich region was the reason for those changes. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [28] Chen, B. et al. The WAVE regulatory complex links diverse receptors to the actin cytoskeleton. Cell 156, 195–207 (2014). sourcePartly supported

  The Results section ('Crystal Structure of the WIRS/WRC Complex Reveals Binding Mechanism'; page unavailable) reports crystallizing a miniWRC that lacks WAVE’s proline-rich region. The Protein Purification section also describes the WRCs as recombinant. Our copy does not say the region was omitted because it is disordered or difficult to crystallize. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [30] Ding, B. et al. Structures reveal a key mechanism of WAVE regulatory complex activation by Rac1 GTPase. Nat. Commun. 13, 5444 (2022). sourcePartly supported

  The Results section (‘Structural solutions to understand Rac1 binding to WRC’; page unavailable) says earlier crystal structures used a minimal WRC lacking WAVE1 residues 187–230, and that this region appears disordered in the paper’s cryo-EM reconstructions. It does not identify that deletion as the entire proline-rich region or say that difficulty in crystallization was the reason for omitting it. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

The WAVE1 complex was identified from brain lysates as an interactor of CDK5 complexed with p35, an activating subunit of CDK5.

“The WAVE1 complex was identified from brain lysates as an interactor of CDK5 complexed with p35, an activating subunit of CDK522.”

• cites [22] Kim, Y. et al. Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology. Nature 442, 814–817 (2006). sourceNot checked — no full text of the source

Like WAVE proteins, paralogous members of each subunit are preferentially but not exclusively expressed in specific cell types in the brain.

“Like WAVE proteins, paralogous members of each subunit are preferentially but not exclusively expressed in specific cell types in the brain (Fig. 1 and Table 1).”

De novo mutations in WAVE genes and other components of the WAVE complex have been identified in patients with developmental disorders such as intellectual disability, epileptic seizures, schizophrenia, and/or autism spectrum disorder.

“De novo mutations in WAVE genes and other components of the WAVE complex have been identified in patients with developmental disorders such as intellectual disability, epileptic seizures, schizophrenia, and/or autism spectrum disorder.”

CDK5 phosphorylation of the native WAVE1 complex purified from the rat brain or recombinant WAVE1 inhibits ARP2/3-mediated actin polymerization in vitro.

“CDK5 phosphorylation of the native WAVE1 complex purified from the rat brain or recombinant WAVE1 inhibits ARP2/3-mediated actin polymerization in vitro22.”

• cites [22] Kim, Y. et al. Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology. Nature 442, 814–817 (2006). sourceNot checked — no full text of the source

CDK5 phosphorylates WAVE1 at Ser310, Ser397 and Ser441 with high basal stoichiometry in the intact brain, brain slices or cultured neurons.

“Notably, CDK5 phosphorylates WAVE1 at Ser310, Ser397 and Ser441 with high basal stoichiometry in the intact brain, brain slices or cultured neurons22.”

• cites [22] Kim, Y. et al. Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology. Nature 442, 814–817 (2006). sourceNot checked — no full text of the source

Three paralogs of WAVE (WAVE1-3) are preferentially but not exclusively expressed in distinct brain cell types.

“Three paralogs of WAVE (WAVE1-3; gene names: Wasf1, Wasf2 and Wasf3, respectively) are preferentially but not exclusively expressed in distinct brain cell types (Fig. 1 and Table 1).”

The WAVE2-ABI2 complex, which controls growth cone activity, is crucial for completing the transition from a multipolar to a bipolar shape prior to the initiation of glia-guided migration.

“The WAVE2-ABI2 complex, which controls growth cone activity, is crucial for completing the transition from a multipolar to a bipolar shape prior to the initiation of glia-guided migration.”

• cites [77] Xie, M. J. et al. WAVE2-Abi2 complex controls growth cone activity and regulates the multipolar-bipolar transition as well as the initiation of glia-guided migration. Cereb. Cortex 23, 1410–1423 (2013). sourceNot checked — no full text of the source

The WAVE2-ABI2 complex is involved in glia-guided radial migration of neurons.

“The WAVE2-ABI2 complex is involved in glia-guided radial migration of neurons77.”

• cites [77] Xie, M. J. et al. WAVE2-Abi2 complex controls growth cone activity and regulates the multipolar-bipolar transition as well as the initiation of glia-guided migration. Cereb. Cortex 23, 1410–1423 (2013). sourceNot checked — no full text of the source

These growth cone activities are regulated by ABL and CDK5 through the phosphorylation of Tyr150 and Ser137 of WAVE2.

“These growth cone activities are regulated by ABL and CDK5 through the phosphorylation of Tyr150 and Ser137 of WAVE2.”

• cites [77] Xie, M. J. et al. WAVE2-Abi2 complex controls growth cone activity and regulates the multipolar-bipolar transition as well as the initiation of glia-guided migration. Cereb. Cortex 23, 1410–1423 (2013). sourceNot checked — no full text of the source

Immunoelectron microscopy revealed WAVE1 localization on the outer membrane of mitochondria.

“Immunoelectron microscopy revealed WAVE1 localization on the outer membrane of mitochondria81.”

• cites [81] Danial, N. N. et al. BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature 424, 952–956 (2003). sourceNot checked — no full text of the source

WAVE1 was identified as a component of a mitochondria-associated complex containing PKA, protein phosphatase-1, the proapoptotic protein BAD and glucokinase in the liver.

“WAVE1 was identified as a component of a mitochondria-associated complex containing PKA, protein phosphatase-1, the proapoptotic protein BAD and glucokinase in the liver81.”

• cites [81] Danial, N. N. et al. BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature 424, 952–956 (2003). sourceNot checked — no full text of the source

WAVE3 is expressed in neuronal cells, particularly GABAergic interneurons.

“Although WAVE3 is expressed in neuronal cells, particularly GABAergic interneurons (Fig. 1b and Table 1), its function is less well characterized than that of WAVE1.”

• cites Fig. 1bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Table 1Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Next-generation sequencing has revealed ten distinct sequence variants within WASF1.

“Next-generation sequencing has revealed ten distinct sequence variants within WASF1.”

WAVE2 is expressed at relatively high levels in microglia, perivascular macrophages, and vascular endothelial cells in the brain.

“WAVE2 is expressed at relatively high levels in microglia, perivascular macrophages and vascular endothelial cells in the brain (Fig. 1b and Table 1).”

• cites Fig. 1bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Table 1Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Dysregulation of the WAVE complex and WAVE complex-mediated cellular processes confers vulnerability to a variety of brain disorders.

“Notably, dysregulation of the WAVE complex and WAVE complex-mediated cellular processes confers vulnerability to a variety of brain disorders.”

Multiple signaling pathways converge on the WAVE complex, resulting in the dynamic regulation of actin polymerization.

“Multiple signaling pathways converge on the WAVE complex, resulting in the dynamic regulation of actin polymerization (Fig. 2).”

An increase in the copy number of CYFIP1 is linked to neurodevelopmental alterations.

“An increase in the copy number of CYFIP1 is linked to neurodevelopmental alterations.”

The CYFIP1 gene is a candidate risk factor for psychopathology associated with the 15q11.2 BP1-BP2 copy number variant.

“The CYFIP1 gene is a candidate risk factor for psychopathology associated with the 15q11.2 BP1-BP2 copy number variant (CNV).”

The imbalance of excitatory and inhibitory synaptic function likely contributes to the pathophysiology of CYFIP mutations or copy number variations associated with autism and SCZ.

“The imbalance of excitatory and inhibitory synaptic function likely contributes to the pathophysiology of CYFIP mutations or copy number variations associated with autism and SCZ.”

The WAVE2-ABI2 complex is therefore important for determining the final location of migrating neurons in the neocortex.

“The WAVE2-ABI2 complex is therefore important for determining the final location of migrating neurons in the neocortex.”

The translocation and membrane recruitment of the WAVE complex are critical for the engagement of WAVE-mediated actin polymerization at specific functional loci.

“The translocation and membrane recruitment of the WAVE complex are critical for the engagement of WAVE-mediated actin polymerization at specific functional loci.”

Dysregulation of protein synthesis in neurons has been implicated in the pathogenesis of various neurodevelopmental disorders.

“Dysregulation of protein synthesis in neurons has been implicated in the pathogenesis of various NDDs112.”

• cites [112] Ehninger, D. & Silva, A. J. Genetics and neuropsychiatric disorders: treatment during adulthood. Nat. Med. 15, 849–850 (2009). sourceNot checked — no full text of the source

WAVE1 dysfunction is associated with various NDDs, presenting as a broad phenotypic spectrum ranging from mild-to-profound intellectual disability, autism spectrum disorder, epilepsy, and developmental delay.

“WAVE1 dysfunction is associated with various NDDs, presenting as a broad phenotypic spectrum ranging from mild-to-profound intellectual disability (ID), autism spectrum disorder (ASD), epilepsy, and developmental delay (DD).”

Five heterozygous missense variants in WASF1 have been reported in patients with neurodevelopmental disorders.

“The remaining five heterozygous missense variants have been reported in patients with NDDs (Table 2d).”

• cites Table 2dNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

CYFIP1 has been implicated in autism.

“CYFIP1 has been implicated in autism107,108.”

• cites [107] Nishimura, Y. et al. Genome-wide expression profiling of lymphoblastoid cell lines distinguishes different forms of autism and reveals shared pathways. Hum. Mol. Genet. 16, 1682–1698 (2007). sourceNot checked — no full text of the source
• cites [108] Nowicki, S. T. et al. The Prader-Willi phenotype of fragile X syndrome. J. Dev. Behav. Pediatr. 28, 133–138 (2007). sourceNot checked — no full text of the source

Microcephaly was not observed in any other patients with WASF1 mutation.

“However, this phenotype was not observed in any other patients with WASF1 mutation.”

Copy number variants in the 15q11.2 region are found in patients with neurodevelopmental disorders, including autism spectrum disorder, schizophrenia, intellectual disability, and epilepsy.

“CNVs in the 15q11.2 region are found in patients with NDDs, including ASD, SCZ, ID, and epilepsy (Table 2i).”

• cites Table 2iNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The mutated residues in WASF1 are located within functionally crucial domains.

“No discernible phenotypic differences have been observed between LoF variants and missense variants, indicating that the mutated residues are located within functionally crucial domains.”

Four nonsense variants in WASF1 (p.Lys46Ter, p.Glu88Ter, p.Met165AsnfsTer8, and p.Ser489Ter) are listed in ClinVar as associated with neurodevelopmental disorders.

“In the ClinVar database, four more nonsense variants associated with NDD were listed: p.Lys46Ter, p.Glu88Ter, p.Met165AsnfsTer8, and p.Ser489Ter (Table 2e).”

• cites ClinVarNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Table 2eNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

WAVE complex-mediated actin polymerization might control the availability of globular actin or F-actin, which is required for nuclear programming or DNA repair.

“Thus, WAVE complex-mediated actin polymerization might control the availability of globular actin (G-actin) or F-actin, which is required for nuclear programming or DNA repair.”

Protein modeling and functional analyses suggest a model of sustained activation of the WAVE complex by Arg87 variants of CYFIP2.

“Based on the LoF intolerance score (pLI = 1) of CYFIP2, the authors initially assumed that variants in Arg87 might lead to impaired WAVE-mediated actin dynamics through an LoF mechanism, but subsequent protein modeling and functional analyses suggest a model of sustained activation of the WAVE complex by Arg87 variants118.”

• cites [118] Nakashima, M. et al. De novo hotspot variants in CYFIP2 cause early-onset epileptic encephalopathy. Ann. Neurol. 83, 794–806 (2018). sourceNot checked — no full text of the source

In a subgroup of fragile X syndrome patients exhibiting severe autism spectrum disorder and obsessive-compulsive behavior, CYFIP1 mRNA is downregulated, particularly in patients with the Prader-Willi phenotype.

“In a subgroup of fragile X syndrome (FXS) patients exhibiting severe ASD and obsessive‒compulsive behavior, the CYFIP1 mRNA is downregulated, particularly in patients with the Prader‒Willi phenotype108.”

• cites [108] Nowicki, S. T. et al. The Prader-Willi phenotype of fragile X syndrome. J. Dev. Behav. Pediatr. 28, 133–138 (2007). sourceNot checked — no full text of the source

A knock-in mouse model of the p.Arg87Cys variant recapitulated many neurological and neurobehavioral phenotypes found in patients with this variant.

“A knock-in mouse model of the p.Arg87Cys variant recapitulated many neurological and neurobehavioral phenotypes found in patients with this variant120.”

• cites [120] Kang, M. et al. CYFIP2 p.Arg87Cys causes neurological defects and degradation of CYFIP2. Ann. Neurol. 93, 155–163 (2023). sourceNot checked — no full text of the source

These CYFIP2 mutations likely lead to loss-of-function of CYFIP2.

“Consequently, these mutations likely lead to the LoF of CYFIP2.”

The loss-of-function mechanism of CYFIP2 was further supported by the finding of protein instability of CYFIP2 variants in cells and in the brain.

“However, the LoF mechanism of CYFIP2 was further supported by the finding of protein instability of CYFIP2 variants in cells119 and in the brain120.”

• cites [119] Lee, Y. et al. Reduced CYFIP2 stability by Arg87 variants causing human neurological disorders. Ann. Neurol. 86, 803–805 (2019). sourceNot checked — no full text of the source
• cites [120] Kang, M. et al. CYFIP2 p.Arg87Cys causes neurological defects and degradation of CYFIP2. Ann. Neurol. 93, 155–163 (2023). sourceNot checked — no full text of the source

Alterations of the WAVE complex have been implicated in the pathophysiology of Alzheimer's disease.

“Alterations of the WAVE complex have been implicated in the pathophysiology of AD.”

Disorganization of neuronal layers and gliosis in the brain were observed in the p.Arg87Cys knock-in mice.

“In addition, disorganization of the neuronal layers and gliosis in the brain were observed in the knock-in mice.”

• cites [120] Kang, M. et al. CYFIP2 p.Arg87Cys causes neurological defects and degradation of CYFIP2. Ann. Neurol. 93, 155–163 (2023). sourceNot checked — no full text of the source

NCKAP1 expression was discovered to be markedly reduced in the brains of AD patients compared with those of normal subjects.

“NCKAP1 expression was also discovered to be markedly reduced in the brains of AD patients compared with those of normal subjects152, but the functional roles of NCKAP1 downregulation in AD remain to be established.”

• cites [152] Suzuki, T. et al. Molecular cloning of a novel apoptosis-related gene, human Nap1 (NCKAP1), and its possible relation to Alzheimer disease. Genomics 63, 246–254 (2000). sourceNot checked — no full text of the source

The activation of RAC1 in a cell line or primary cultured cortical neurons increased Aβ levels and tau hyperphosphorylation.

“The activation of RAC1 in a cell line or primary cultured cortical neurons increased Aβ levels and tau hyperphosphorylation.”

• cites [151] Boo, J. H., Sohn, J. H., Kim, J. E., Song, H. & Mook-Jung, I. Rac1 changes the substrate specificity of gamma-secretase between amyloid precursor protein and Notch1. Biochem. Biophys. Res. Commun. 372, 913–917 (2008). sourceNot checked — no full text of the source

Psychostimulant drug-induced behavioral responses require WAVE1 complex-mediated synaptic modulation.

“Psychostimulant drug-induced behavioral responses require WAVE1 complex-mediated synaptic modulation.”

Alterations in WAVE1, ABI1/2 and CYFIP1/2 in neurons or ABI3 and WAVE2 in microglia have been implicated in the pathophysiology of NDDs, AD or PD.

“Alterations in WAVE1, ABI1/2 and CYFIP1/2 in neurons or ABI3 and WAVE2 in microglia have been implicated in the pathophysiology of NDDs, AD or PD.”

The evidence for pivotal contributions of alterations in the WAVE complex to the development of NDDs and neurodegenerative diseases is growing.

“The evidence for pivotal contributions of alterations in the WAVE complex to the development of NDDs and neurodegenerative diseases is growing (Fig. 4b).”

• cites Fig. 4bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

It is not technically feasible to assess WAVE complex activity in vivo, which is affected by multiple regulatory inputs, including protein activators, phospholipids, phosphorylation or dephosphorylation, and membrane-associated interactors.

“However, it is not technically feasible to assess WAVE complex activity in vivo, which is affected by multiple regulatory inputs, including protein activators, phospholipids, phosphorylation or dephosphorylation, and membrane-associated interactors (Fig. 2).”

• cites Fig. 2Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.