Modeling Autism by SHANK Gene Mutations in Mice
Open accessAbstract
Shank family proteins (Shank1, Shank2, and Shank3) are synaptic scaffolding proteins that organize an extensive protein complex at the postsynaptic density (PSD) of excitatory glutamatergic synapses. Recent human genetic studies indicate that SHANK family genes (SHANK1, SHANK2, and SHANK3) are causative genes for idiopathic autism spectrum disorders (ASD). Neurobiological studies of Shank mutations in mice support a general hypothesis of synaptic dysfunction in the pathophysiology of ASD. However, the molecular diversity of SHANK family gene products, as well as the heterogeneity in human and mouse phenotypes, pose challenges to modeling human SHANK mutations. Here, we review the molecular genetics of SHANK mutations in human ASD and discuss recent findings where such mutations have been modeled in mice. Conserved features of synaptic dysfunction and corresponding behaviors in Shank mouse mutants may help dissect the pathophysiology of ASD, but also highlight divergent phenotypes that arise from different mutations in the same gene.
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- Findingcitation
Mouse Shank2a exons 6 and 7 correspond to exons 16 and 17 of predicted full-length mouse Shank2 based on rat cDNA.
“Using the longest rat cDNA of Shank2 deposited in GenBank (NM_201350) as a reference, one can deduce that exons 6 and 7 in mouse Shank2a isoform correspond to exons 16 and 17 of predicted full length mouse Shank2 deduced from rat cDNA (NM_201350)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites NM_201350
Not checked in the free run.
- Rests on an assumption: The rat Shank2 cDNA reference accurately predicts the exon numbering of full-length mouse Shank2.
- Interpretationreasoning
The molecular diversity of SHANK gene products and the heterogeneity of human and mouse phenotypes make it difficult to model human SHANK mutations.
“However, the molecular diversity of SHANK family gene products, as well as the heterogeneity in human and mouse phenotypes, pose challenges to modeling human SHANK mutations.”
Quote in the paperSubstantial claim - Premisecitation
Little is known about the underlying pathophysiology or neurological basis of ASD.
“Remarkably little is known about the underlying pathophysiology or neurological basis of ASD (Amaral et al., 2008; Courchesne et al., 2007; Geschwind and Levitt, 2007; Rubenstein, 2010; Zoghbi, 2003).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Shank1, Shank2, and Shank3 are synaptic scaffolding proteins that assemble a large protein complex at the postsynaptic density of excitatory glutamatergic synapses.
“Shank family proteins (Shank1, Shank2, and Shank3) are synaptic scaffolding proteins that organize an extensive protein complex at the postsynaptic density (PSD) of excitatory glutamatergic synapses.”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Human genetic studies indicate that SHANK1, SHANK2, and SHANK3 are causative genes for idiopathic autism spectrum disorders.
“Recent human genetic studies indicate that SHANK family genes (SHANK1, SHANK2, and SHANK3) are causative genes for idiopathic autism spectrum disorders (ASD).”
Quote in the paperSubstantial claim0 of 3 sources checked
- Interpretationreasoning
Neurobiological studies of Shank mutations in mice support a general hypothesis that synaptic dysfunction underlies the pathophysiology of autism spectrum disorders.
“Neurobiological studies of Shank mutations in mice support a general hypothesis of synaptic dysfunction in the pathophysiology of ASD.”
Quote in the paperSubstantial claim - Premisecitation
SHANK/ProSAP family proteins are promising candidates for modeling ASD in mice because of strong genetic evidence of SHANK molecular defects in ASD patients.
“SHANK/ProSAP family proteins (SHANK1, SHANK2, SHANK3) have emerged as promising candidates for modeling ASD in mice due to strong genetic evidence showing molecular defects of SHANK in patients with ASD (Berkel et al., 2010; Berkel et al., 2012; Durand et al., 2007; Gauthier et al., 2010; Marshall et al., 2008; Pinto et al., 2010; Sato et al., 2012).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationcitation
For point mutations such as missense mutations and small intragenic deletions in SHANK2 and SHANK3, the pathogenic mechanism is less clear.
“By comparison, for point mutations such as missense mutation and small intragenic deletions identified in SHANK2 and SHANK3, the pathogenic mechanism is less clear (Bonaglia et al., 2011; Durand et al., 2011; Moessner et al., 2007).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
Mutations in SHANK1 and SHANK2 have also been associated with ASD.
“Recently, mutations in SHANK1 and SHANK2 have also been associated with ASD (Berkel et al., 2010; Berkel et al., 2012; Sato et al., 2012), supporting a general function for this gene family in common molecular pathways associated with ASD.”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Pathological point mutations in SHANK1 have not yet been reported in ASD.
“Pathological point mutations have not yet been reported in ASD so far (Sato et al., 2012)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sato et al., 2012 source
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- Premisenone given
No studies relating genotype and phenotype have been reported for SHANK1 and SHANK2 mutations associated with ASD.
“In the cases of SHANK1 and SHANK2 mutations associated with ASD, no studies relating genotype and phenotype have been reported.”
Quote in the paperNot a substantial claim - Premisecitation
Point mutations, including a nonsense mutation in exon 21 (p.R1117X) of SHANK3, have been reported in families with schizophrenia and mild intellectual disability.
“Interestingly, point mutations, including a nonsense mutation in exon 21 (p.R1117X) of SHANK3 have been reported in families with schizophrenia and mild intellectual disability (Gauthier et al., 2010).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Gauthier et al., 2010 source
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- Interpretationreasoning
The genetic association of ASD with SHANK family genes provided a direct link between synaptic dysfunction and ASD pathophysiology.
“The genetic association of ASD with SHANK family genes provided an immediate link between synaptic dysfunction and the pathophysiology of ASD.”
Quote in the paperSubstantial claim - Premisecitation
The penetrance of SHANK2 mutations in ASD is not complete in some cases.
“The penetrance of SHANK2 mutations in ASD is not complete in some cases (Leblond et al., 2012).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Leblond et al., 2012 source
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- Interpretationcitation
Deletions involving entire SHANK family genes in ASD predict that haploinsufficiency is the primary mechanism underlying ASD pathogenesis.
“Deletions involving entire SHANK family genes in ASD predict that haploinsufficiency is the primary mechanism underlying ASD pathogenesis (Wilson et al., 2003).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wilson et al., 2003 source
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- Interpretationreasoning
Because clinical data are incomplete in most cases, it is difficult to draw firm conclusions about the relationship between specific SHANK3 variants and ASD-related clinical features.
“Because the clinical data are not complete in most cases, it is difficult to draw firm conclusions about the relationship between specific SHANK3 variants and clinical features related to ASD.”
Quote in the paperSubstantial claim - Premisecitation
SHANK3 mutations contribute only a small degree to the population attributable risk of ASD.
“and the degree to which SHANK3 mutations contribute to the population attributable risk of ASD is small (Betancur, 2011; Buxbaum, 2009; State, 2010b).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
In other cases with almost identical small microdeletions including SHANK3, neurobehavioral phenotypes were quite variable.
“Similarly, in other cases with almost identical small microdeletions (<100 kb) including SHANK3, neurobehavioral phenotypes were quite variable (Boccuto et al., 2013; Bonaglia et al., 2011; Dhar et al., 2010).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
Microdeletions including SHANK1 and two other adjacent genes were reported in five ASD individuals from two families with mild ASD.
“In the case of SHANK1, microdeletions including SHANK1 and two other adjacent genes were reported in five ASD individuals in two families with mild ASD (Figure 1C).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sato et al., 2012 source
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- Premisecitation
A nonsense mutation in SHANK2 exon 24, encoding the proline-rich homer-binding domain, has been found in an ASD proband.
“A nonsense mutation in SHANK2 exon 24 encoding the proline-rich homer-binding domain has also been found in an ASD proband (Figure 1B) (Berkel et al., 2010).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Berkel et al., 2010 source
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- Premisereasoning
Three cases with very similar mutations in exon 21 of SHANK3 (p.A1227fs, p.E1311fs, and p.R1117X) illustrate the challenge of genotype-phenotype correlation.
“This challenge is best illustrated in three cases with very similar mutations (p.A1227fs, p.E1311fs, and p.R1117X) in exon 21 encoding Homer binding site of SHANK3 (Figure 1A).”
Quote in the paperNot a substantial claim - Premisecitation
The frequency of putatively pathological SHANK3 mutations in ASD appears to be rare, less than 0.75%.
“However, the frequency of putatively pathological mutations in SHANK3 appears to be rare in ASD (< 0.75%) (Moessner et al., 2007)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Moessner et al., 2007 source
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- Premisecitation
Point mutations and microdeletions of SHANK3 have been identified in idiopathic ASD cases.
“Subsequently, point mutations and microdeletions of SHANK3 have been identified in idiopathic ASD cases (Boccuto et al., 2012; Dhar et al., 2010; Durand et al., 2007; Gauthier et al., 2010; Gong et al., 2012; Marshall et al., 2008; Moessner et al., 2007; Waga et al., 2011).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
De novo sequence changes in SHANK3, including missense, frame shift, and splice site mutations, have been reported in ASD patients.
“De novo sequence changes in SHANK3 including missense, frame shift, and splice site mutations have been reported in ASD patients (Boccuto et al., 2012; Durand et al., 2007; Gauthier et al., 2010; Gauthier et al., 2009; Gong et al., 2012; Hamdan et al., 2011; Moessner et al., 2007; Schaaf et al., 2011; Waga et al., 2011).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Microduplications of SHANK3 have been reported in children with developmental delay and dysmorphic features.
“Microduplications of SHANK3 have also been reported in children with developmental delay and dysmorphic features (Okamoto et al., 2007)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Okamoto et al., 2007 source
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- Premisecitation
Microdeletion of SHANK1 is only penetrant in males with mild ASD in the families studied.
“Interestingly, microdeletion of SHANK1 is only penetrant in males with mild ASD in families studied (Sato et al., 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sato et al., 2012 source
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- Premisecitation
Shank family proteins are scaffolding proteins that organize a cytoskeleton-associated signaling complex at the postsynaptic density of nearly all excitatory glutamatergic synapses in the mammalian brain.
“Shank family proteins are scaffolding proteins that organize a cytoskeleton-associated signaling complex at the postsynaptic density (PSD) of nearly all excitatory glutamatergic synapses in the mammalian brain (Grabrucker et al., 2011b; Gundelfinger et al., 2006; Kreienkamp, 2008; Sheng and Kim, 2000).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisenone given
All microdeletions found in ASD are intragenic deletions that disrupt the SHANK2 protein.
“All microdeletions found in ASD are intragenic deletions that disrupt the SHANK2 protein.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Clinical features from case reports suggest a genotype-phenotype correlation related to the autism diagnosis.
“the clinical features from these cases reports suggest a genotype-phenotype correlation related to the autism diagnosis.”
Quote in the paperNot a substantial claim - Premisecitation
Deletions of SHANK3 have been reported in all PMS cases except one report of two children with deletions proximal to SHANK3.
“deletions of SHANK3 have been reported in all cases except in one report of two children who have deletions proximal to SHANK3 (Wilson et al., 2008)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wilson et al., 2008 source
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- Interpretationcitation
SHANK3 gene dosage affects brain function.
“suggesting that SHANK3 gene dosage affects brain function.”
Quote in the paperSubstantial claim - Interpretationreasoning
Haploinsufficiency of SHANK3 is a major contributor to the neurobehavioral features in 22q13.3 deletion patients.
“These observations have led to the conclusion that haploinsufficiency of SHANK3 is a major contributor to the neurobehavioral features in 22q13.3 deletion patients.”
Quote in the paperSubstantial claim - Premisecitation
SHANK3 maps to the critical region of 22q13.3 deletion syndrome (Phelan-McDermid syndrome).
“SHANK3 maps to the critical region of 22q13.3 deletion syndrome (Phelan-McDermid syndrome, PMS) (Figure 1A) (Wilson et al., 2003).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Wilson et al., 2003 source
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- Premisereasoning
Six types of molecular defects have been identified in SHANK3 in more than 1000 human patients.
“In all, six types of molecular defects have been identified in SHANK3 in more than 1000 human patients.”
Quote in the paperNot a substantial claim - Premisecitation
RNA in situ hybridization in rat brain using a probe from exon 21 showed that Shank3 is widely expressed at low levels at birth and increases after 2 weeks of age in the striatum, hippocampus, cerebellum, and neocortical layers 1 and 2.
“RNA in situ hybridization in rat brain using a single probe from exon 21 encoding the proline-rich domain showed that Shank3 is widely expressed in all brain regions at a low level at birth but increases after 2 weeks of age in the striatum, hippocampus, cerebellum, and in layers 1 and 2 of the neocortex (Bockers et al., 2001; Bockers et al., 2004).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
Shank3e and Shank3f mRNAs lack exons encoding the PDZ domain responsible for interaction with NMDA and AMPA receptors.
“For example, Shank3e and Shank3f mRNAs lack exons encoding the PDZ domain that is responsible for the interaction with NMDA and AMPA receptors (Naisbitt et al., 1999).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Naisbitt et al., 1999 source
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- Premisecitation
Shank3b lacks the proline-rich and SAM domains critical for Homer binding and multimerization.
“Shank3b lacks the proline-rich and SAM domains that are critical for Homer binding and multimerization (Tu et al., 1999).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Tu et al., 1999
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- Premisenone given
More than 30 synaptic proteins have been reported to interact with Shank family proteins.
“More than 30 synaptic proteins have been reported to interact with Shank family proteins (Figure 2 and Table 2).”
Quote in the paperNot a substantial claim - Premisecitation
Expression of Shank3 with deletions of various domains in cultured mouse neurons demonstrates distinct roles for each domain in dendritic spine development.
“Expression of Shank3 with deletions of various domains in cultured mouse neurons has demonstrated distinct roles for each domain in dendritic spine development (Roussignol et al., 2005).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Roussignol et al., 2005 source
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- Interpretationreasoning
Intron 5 splicing mutations in the exon encoding the ANK domain are predicted to affect only the two long SHANK3 isoforms initiated from promoters 1 and 2 (SHANK3a and SHANK3b).
“For example, the intron 5 splicing mutations in the exon encoding the ANK domain is only predicted to affect two long isoforms of SHANK3 initiated from promoters 1 and 2 (SHANK3a and SHANK3b) (Figures 1A and 2B).”
Quote in the paperNot a substantial claim - Interpretationreasoning
The molecular consequences at the RNA and protein levels for each SHANK3 mutation are almost certainly different.
“Therefore, the molecular consequences at the RNA and protein levels for each SHANK3 mutation are almost certainly different.”
Quote in the paperSubstantial claim - Premisecitation
Shanks interact directly or indirectly with all major glutamate receptor types-NMDA receptors, AMPA receptors, and mGluRs-via different domains.
“Concentrated at glutamatergic synapses, Shanks interact directly or indirectly with all major types of glutamate receptors – NMDA receptors, AMPA receptors, and mGluRs – via different domains (Ehlers, 1999; Naisbitt et al., 1999; Tu et al., 1999; Uchino et al., 2006; Verpelli et al., 2011).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationcitation
Because each protein domain mediates a unique set of protein-protein interactions, each Shank3 isoform likely has a distinct set of functions.
“Because each protein domain mediates a unique complement of protein-protein interactions (Hayashi et al., 2009; Roussignol et al., 2005), it is likely that each Shank3 isoform has a distinct set of functions.”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
Selected mRNA isoforms analyzed in silico indicate that each Shank3 isoform (Shank3a-f) has a unique combination of protein domains.
“The exact number of protein isoforms has not been determined, but selected mRNA isoforms analyzed in silico indicate that each Shank3 isoform (Shank3a-f) has a unique combination of different protein domains as illustrated in Figure 2B (Wang et al., 2011).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wang et al., 2011 source
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- Interpretationreasoning
Microdeletions or large cytogenetic deletions will disrupt all SHANK3 isoforms.
“In contrast, microdeletions or large cytogenetic deletions will disrupt all SHANK3 isoforms.”
Quote in the paperNot a substantial claim - Premisecitation
Shank3-interacting proteins include receptors, ion channels, cytoskeletal proteins, scaffolding proteins, enzymes, and signaling molecules.
“Shank3-interacting proteins include receptors, ion channels, cytoskeletal proteins, scaffolding proteins, enzymes, and signaling molecules (Grabrucker et al., 2011b; Kreienkamp, 2008).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Grabrucker et al., 2011b
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- cites Kreienkamp, 2008 source
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- Premisecitation
SHANK genes have complex transcriptional regulation with multiple intragenic promoters and extensive alternatively spliced exons in both humans and mice.
“SHANK genes display a complex transcriptional regulation with multiple intragenic promoters and extensive alternatively spliced exons both in humans and mice (Leblond et al., 2012; Lim et al., 1999; Maunakea et al., 2010; McWilliams et al., 2004; Redecker et al., 2006; Wang et al., 2011; Wilson et al., 2003).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
Little information is available on the molecular mechanisms by which more subtle SHANK3 mutations alter protein function at synapses.
“However, to date, we have little information on the molecular mechanisms by which more subtle mutations in SHANK3 alter protein function at synapses (Durand et al., 2007; Durand et al., 2011).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Durand et al., 2007 source
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- cites Durand et al., 2011
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- Premisenone given
The alternatively spliced exons of Shank3 encode the SH3, proline-rich, and SAM domains.
“The alternatively spliced exons of Shank3 encode the SH3, proline-rich, and SAM domains (Figure 1A).”
Quote in the paperNot a substantial claim - Interpretationreasoning
Mutations in exon 21 are expected to have no effect on mRNAs lacking exon 21 or on other short SHANK3 mRNAs truncated before exon 21.
“Mutations in exon 21 are expected to have no effect on mRNAs lacking exon 21 or other short SHANK3 mRNAs truncated before exon 21.”
Quote in the paperNot a substantial claim - Premisereasoning
In vitro binding experiments show significant overlap in protein-protein interactions involving Shank1-3 due to similarity of their protein domains.
“Due to the similarity of protein domains among Shank family proteins, in vitro binding experiments have shown a significant overlap in protein-protein interactions involving Shank1-3.”
Quote in the paperNot a substantial claim - Interpretationreasoning
The complexity of SHANK3 transcript structure indicates that point mutations, translocations, and intragenic deletions found in ASD patients are isoform-specific.
“The complexity of SHANK3 transcript structure indicates that point mutations, translocations, and intragenic deletions of SHANK3 found in ASD patients are isoform-specific.”
Quote in the paperSubstantial claim - Premisecitation
Shanks are scaffolding proteins that interact with many synaptic proteins in the postsynaptic density.
“Shanks are scaffolding proteins that interact with many synaptic proteins in the PSD (Ehlers, 1999; Gundelfinger et al., 2006; Kreienkamp, 2008; Sheng and Kim, 2000).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationcitation
In addition to alternative promoter use and mRNA splicing, epigenetic mechanisms such as DNA methylation and histone acetylation regulate Shank3 expression in an isoform-specific manner.
“Thus, in addition to alternate promoter use and mRNA splicing, epigenetic mechanisms such as DNA methylation and histone acetylation regulate the expression of the Shank3 gene in an isoform-specific manner.”
Quote in the paperNot a substantial claim - Premisecitation
Two Shank2 mutant mouse lines have been reported.
“Two different lines of Shank2 mutant mice have been recently reported (Schmeisser et al., 2012; Won et al., 2012).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
SHANK2 exhibits transcriptional regulation similar to SHANK3.
“SHANK2 exhibits transcriptional regulation similar to SHANK3 (Leblond et al., 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Leblond et al., 2012 source
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- Interpretationreasoning
The two Shank2 targeted mutations are predicted to be very similar at protein level.
“Therefore, the molecular nature of these two targeted mutations is predicted to be very similar at protein level.”
Quote in the paperSubstantial claim - Premisecitation
In Shank2 Δex6-7−/− hippocampus, phosphorylated CaMKIIα/β (T286), ERK1/2, p38, and GluA1 (Ser831/S845) are reduced.
“In Shank2 Δex 6-7−/− mice, reduction of phosphorylated CaMKIIα/β (T286), ERK1/2, p38, and GluA1 (Ser831/S845) was observed in hippocampus (Won et al., 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Won et al., 2012 source
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- Premisecitation
DNA methylation and histone deacetylase inhibitors modulate isoform-specific Shank3 expression in cultured neurons.
“Both DNA methylation and histone deacetylase inhibitors have been shown to modulate the isoform specific gene expression of Shank3 in cultured neurons (Beri et al., 2007; Maunakea et al., 2010).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
Won et al. generated Shank2 Δex6-7 mice.
“Won et al. described mice with both exons 6 and 7 deleted (Shank2 Δex6-7).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Won et al., 2012 source
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- Interpretationcitation
Differences in SHANK2 exon numbering across organisms in other reports likely reflect uncharacterized exons or alternative splicing.
“The difference in exon numbering for SHANK2 in different organisms in other reports is likely due to the pattern of uncharacterized exons or alternative splicing (Leblond et al., 2012; Lim et al., 1999; McWilliams et al., 2004).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
GluN1 is increased in hippocampus of Shank2 Δex6-7−/− mice.
“Similar to Shank2 Δex7−/− mice (Schmeisser et al., 2012), GluN1 is increased in the hippocampus of Shank2 Δex6-7−/− mice (Won et al., 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Won et al., 2012 source
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- Interpretationcitation
Available evidence indicates that the overall transcriptional structure of SHANK family genes is conserved in mice.
“Together, the available evidence indicates that the overall transcriptional structure of SHANK family genes is conserved in mice (Wang et al., 2011).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wang et al., 2011 source
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- Premisecitation
Schmeisser et al. generated Shank2 Δex7 mice.
“Schmeisser et al. reported Shank2 exon 7 deletion mutant mice (Shank2 Δex7)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Schmeisser et al., 2012 source
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- Interpretationcitation
Peak expression of Shank3 occurs at an important developmental stage of synaptic plasticity and experience-dependent circuit maturation.
“Peak expression of Shank3 occurs at an important developmental stage of synaptic plasticity and experience-dependent circuit maturation (Bockers et al., 2004).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Bockers et al., 2004 source
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- Interpretationreasoning
The complexity of transcriptional regulation poses a significant technical challenge to adequately modeling human SHANK mutations in mice.
“However, the complexity of transcriptional regulation poses a significant technical challenge to adequately model human SHANK mutations in mice.”
Quote in the paperNot a substantial claim - Premisenone given
Mutant mice for all Shank family genes have now been produced and characterized.
“Mutant mice for all Shank family genes have now been produced and characterized (Figure 3).”
Quote in the paperNot a substantial claim - Premisecitation
Shank3 is up-regulated in striatum of Shank2 Δex7−/− mice.
“Interestingly, Shank3 was up-regulated in striatum of Shank2 Δex7−/− mice.”
- Also stated in: § Synaptic Proteins in Shank3-Deficient Mouse Brain · plain
“while Shank3 was found to be increased in Shank2 Δex7−/− mutant mice (Schmeisser et al., 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Schmeisser et al., 2012 source
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- Also stated in: § Synaptic Proteins in Shank3-Deficient Mouse Brain · plain
- Premisecitation
SHANK2 has several isoforms driven by multiple promoters and alternative splicing of coding exons.
“Specifically, SHANK2 has several isoforms driven by multiple promoters and alternative splicing of coding exons (Figure 1B).”
Quote in the paperNot a substantial claim - Premisecitation
Spatial learning and memory were enhanced in Shank1−/− mice.
“Intriguingly, spatial learning and memory was enhanced in Shank1−/− mice (Hung et al., 2010).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hung et al., 2010
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- Premisecitation
The synaptic proteins GKAP/SAPAP and Homer are reduced in the PSD of Shank1−/− mouse brain.
“The synaptic proteins GKAP/SAPAP and Homer are reduced in the PSD of Shank1−/− mouse brain.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hung et al., 2008 source
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- Premisecitation
Decreased PSD thickness and length are observed at corticostriatal synapses in Δex13-16−/− mice.
“Decreased PSD thickness and length were observed at corticostriatal synapses in Δex13-16−/− mice (Peca et al., 2011)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Peca et al., 2011 source
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- Premisecitation
GluN2B is increased in synaptosomal fractions from Δex11−/− hippocampus.
“In contrast, GluN2B was increased in synaptosomal fractions from Δex11−/− hippocampus (Schmeisser et al., 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Schmeisser et al., 2012 source
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- Interpretationreasoning
Ultrastructural and morphological analysis indicates complex regulation of glutamatergic synapse size, shape, and structure.
“The totality of ultrastructural and morphological analysis in Shank3 mutant mice indicates complex regulation of glutamatergic synapse size, shape, and structure.”
Quote in the paperSubstantial claim - Premisecitation
Dendritic branching and spine area are increased in medium spiny neurons of striatum of Δex13-16−/− mice.
“Dendritic branching and spine area was increased in medium spiny neurons (MSNs) of the striatum of Δex13-16−/− mice (Peca et al., 2011)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Peca et al., 2011 source
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- Premisecitation
Cryptic splicing from exon 2 to 10 in Δex4-9J−/− mice occurs in brain but not kidney.
“Intriguingly, this cryptic splicing from exon 2 to 10 occurred only in brain but not in kidney of Δex4-9J−/− mice.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wang et al., 2011 source
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- Interpretationcitation
PSD proteins are altered in different brain regions of all Shank3 mutant mice but to varying degrees.
“PSD proteins were altered in different brain regions of all Shank3 mutant mice but to varying degrees”
Quote in the paperNot a substantial claim - Premisecitation
Spine length is increased in CA1 hippocampus of Δex4-9J−/− mice.
“Spine length was increased in CA1 hippocampus of Δex4-9J−/− mice (Wang et al., 2011)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wang et al., 2011 source
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- Premisecitation
GluA1 is reduced in hippocampal neurons in culture and hippocampal tissues from Δex4-9J−/− and Δex4-9B+/− mice.
“The AMPA receptor subunit GluA1 was reduced in hippocampal neurons examined in culture and hippocampal tissues from Δex4-9J−/− (Wang et al., 2011) and Δex4-9B+/− mice (Bozdagi et al., 2010)”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationreasoning
Changes in levels of synaptic proteins and receptors are relatively modest in nearly all mouse lines and brain areas examined.
“In nearly all mouse lines and brain areas examined, changes in the level of these synaptic proteins and receptors was relatively modest”
Quote in the paperNot a substantial claim - Interpretationcitation
Changes in Homer1 and Shank3 across several mouse lines and brain regions are consistent with the known multimeric network formed between these two proteins.
“The corresponding changes of Homer1 and Shank3 in several mouse lines and several brain regions are consistent with the known multimeric network formed between these two proteins (Hayashi et al., 2009; Tu et al., 1999).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Hayashi et al., 2009 source
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- cites Tu et al., 1999
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- Interpretationcitation
Shank3 mutations alter levels of synaptic glutamate receptors.
“Mutations of Shank3 altered the levels of synaptic glutamate receptors.”
Quote in the paperSubstantial claim - Study design and conductcitation
Phenotypic analyses were performed extensively on heterozygotes or homozygotes at different ages for Shank3 Δex4-7, Δex4-9J, Δex4-9B, and Δex13-16, but less in Δex11.
“Phenotypic analyses at the biochemical, synaptic, and behavioral levels were performed extensively on either heterozygotes or homozygotes at different ages for Shank3 Δex4-7, Δex4-9J, Δex4-9B, and Δex13-16 but to a lesser degree in Δex11 mutant mice”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
Activity-induced spine growth by theta burst stimulation in cultured brain slices is attenuated at CA1 synapses of Δex4-9B+/− mice.
“Activity-induced spine growth by theta burst stimulation in cultured brain slices was attenuated at CA1 synapses of Δex4-9B+/− mice (Bozdagi et al., 2010).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Bozdagi et al., 2010 source
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- Interpretationcitation
Each of these Shank3 mutant lines is expected to disrupt different Shank3 isoforms.
“Based on current knowledge of Shank3 promoters and alternative splicing, each of these mice is expected to have disruption of different Shank3 isoforms (Wang et al., 2011)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Wang et al., 2011 source
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- Premisecitation
Both GluN2A and GluN2B are reduced in striatum of Δex13-16−/− mice.
“Both GluN2A and GluN2B subunits were reduced in the striatum of Δex13-16−/− mice (Peca et al., 2011)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Peca et al., 2011 source
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- Premisecitation
Homer1, GKAP/SAPAP, and PSD-93 are reduced in PSD fractions from striatum of Δex13-16−/− mice.
“Homer1, GKAP/SAPAP, and PSD-93 were reduced in PSD fractions isolated from the striatum of Δex13-16−/− mice (Peca et al., 2011)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Peca et al., 2011 source
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- Premisecitation
Homer1b/c and GKAP1/SAPAP1 are reduced in PSD fraction but not cytosolic fraction of Δex4-9J−/− hippocampus.
“Homer1b/c and GKAP1/SAPAP1 were reduced in the PSD fraction but not in the cytosolic fraction of Δex4-9J−/− hippocampus (Wang et al., 2011).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wang et al., 2011 source
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- Premisecitation
Isoform-specific disruption of Shank3 was evident in Δex4-7, Δex4-9J, Δex11, and Δex13-16 mice.
“Isoform-specific disruption of Shank3 was evident in Δex4-7, Δex4-9J, Δex11, and Δex13-16 mice (Peca et al., 2011; Schmeisser et al., 2012; Wang et al., 2011).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
GluN2A is reduced in hippocampus of Δex4-9J−/− mice.
“In the case of NMDA receptors, GluN2A subunit was reduced in the hippocampus of Δex4-9J−/− mice (Wang et al., 2011).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wang et al., 2011 source
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- Premisecitation
Reduction of spine density in Δex4-9J−/− mice is developmental stage-specific, with significant loss at 4 weeks but not 10 weeks.
“The reduction of spine density visualized by Golgi impregnation was developmental stage-specific in Δex4-9J−/− mice, with significant spine loss observed at 4 weeks but not at 10 weeks of age (Wang et al., 2011).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wang et al., 2011 source
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- Interpretationcitation
Δex13-16 mutation is predicted to disrupt transcripts from promoter 1 to 4 (Shank3a-d) but not from promoter 5 to 6 (Shank3e-f).
“while the Δex13-16 mutation (Peca et al., 2011) is predicted to disrupt transcripts from promoter 1 to 4 (Shank3a-d) but not from promoter 5 to 6 (Shank3e-f)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Peca et al., 2011 source
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- Interpretationreasoning
The cryptic splicing observation suggests otherwise similar Shank3 mutations may have different molecular consequences at mRNA and protein level.
“This observation adds to the complexity of predicting the molecular consequence of different mutations in Shank3 mutant mice, and perhaps in human SHANK3 mutations, and suggests that otherwise similar mutations such as Δex4-9B, Δex4-9J, and Δex4-7 may have different molecular consequences for Shank3 at the mRNA and protein level.”
Quote in the paperSubstantial claim - Interpretationreasoning
Specific patterns of altered synaptic proteins vary among different mutant mice lines with similar mutations.
“The specific patterns of altered synaptic proteins varied among different mutant mice lines with similar mutations.”
Quote in the paperSubstantial claim - Interpretationreasoning
A compensatory mechanism may contribute to reciprocal changes in Shank2 Δex7−/− and Shank3 Δex11−/− mice.
“This compensatory mechanism may contribute to the reciprocal changes in Shank2 Δex7−/− and Shank3 Δex11−/− mice.”
Quote in the paperNot a substantial claim - Premisecitation
GluA2 is reduced in striatum of Δex13-16−/− mice.
“and GluA2 was reduced in the striatum of Δex13-16−/− mice (Peca et al., 2011).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Peca et al., 2011 source
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- Premisecitation
Δex4-9J mice show an unexpected mRNA splice isoform from exon 2 to exon 10, in addition to the expected exon 3 to 10.
“One unexpected finding from RNA expression analysis of Δex4-9J mice was the presence of an mRNA splice isoform from exon 2 to exon 10, in addition to the expected splicing isoform from exon 3 to exon 10 due to the deletion of exons 4-9 (Wang et al., 2011).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wang et al., 2011 source
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- Interpretationreasoning
These effects, together with spine elongation, suggest a phenotype of reduced or delayed synapse maturation reminiscent of fragile X, Rett, and Angelman syndrome models.
“These effects, together with spine elongation, suggests a phenotype of reduced or delayed synapse maturation that is reminiscent of the phenotypes observed in mouse models of fragile X syndrome (Comery et al., 1997; Irwin et al., 2001), Rett syndrome (Armstrong, 2005; Belichenko et al., 2009; Chao et al., 2007), and Angelman syndrome (Dindot et al., 2008; Sato and Stryker, 2010; Yashiro et al., 2”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Shank2 is increased in synaptosomal fraction of Δex11−/− striatum.
“Interestingly, Shank2 was increased in the synaptosomal fraction of Δex11−/− striatum”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Schmeisser et al., 2012 source
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- Premisecitation
Δex4-9J deletion disrupts mRNA transcripts from promoters 1 and 2 (Shank3a and Shank3b) but not Shank3c-f.
“The Δex4-9J deletion disrupted mRNA transcripts from promoters 1 and 2 (Shank3a and Shank3b) but not Shank3c-f as confirmed by isoform-specific RT-PCR analysis (Wang et al., 2011).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wang et al., 2011 source
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- Premisecitation
Five Shank3 mutant mouse lines with different mutations have been reported.
“Five lines of Shank3 mutant mice carrying different mutations in Shank3 have been reported (Bozdagi et al., 2010; Peca et al., 2011; Schmeisser et al., 2012; Wang et al., 2011)”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
GKAP/SAPAP is not reduced in striatum of Δex11−/− mice.
“but GKAP/SAPAP was not reduced in striatum of Δex11−/− mice (Schmeisser et al., 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Schmeisser et al., 2012 source
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- Premisecitation
Synaptic dysfunction and abnormal behaviors have been documented in mice harboring Disc1 mutations.
“Synaptic dysfunction and abnormal behaviors have been documented in mice harboring Disc1 mutations (Clapcote et al., 2007; Kim et al., 2009)”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Repetitive behaviors were not apparent in Δex4-7−/− mice.
“but were not apparent in Δex4-7−/− mice (Peca et al., 2011).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Peca et al., 2011 source
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- Study design and conductreasoning
Firm conclusions about isoform-specific effects are complicated by different isoforms being expressed, different ages, and slightly different protocols.
“Firm conclusions in this regard are complicated by the fact that the different Shank3 isoforms are probably expressed in various Shank3 mutant mice, which were analyzed at different ages using slightly different protocols.”
Quote in the paperSubstantial claim - Premisecitation
There is currently no reliable biomarker, pathology, anatomical finding, or functional neuroimaging change that is pathognomonic or predictive for ASD.
“There is currently no reliable biomarker, pathology, anatomical finding, or functional neuroimaging change that can be considered pathognomonic or predictive for ASD (Anagnostou and Taylor, 2011; Bauman and Kemper, 2005; Courchesne et al., 2007; Lord et al., 2000a).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Prepulse inhibition is not affected in Δex4-9J−/− and Δex4-9B−/− mice.
“Prepulse inhibition (PPI) is not affected in Δex4-9J−/− (Wang et al., 2011) and Δex4-9B−/− (Yang et al., 2012) mice”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
Reduced ultrasonic vocalizations in adult were reported in Δex4-9B mice.
“Reduced ultrasonic vocalizations adult were also reported in Δex4-9B (Bozdagi et al., 2010; Yang et al., 2012).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationcitation
Δex4-9 and Δex4-7 mouse mutations are closest to patients with intragenic exon 1-9 deletion and splice mutation of intron 5 in SHANK3.
“The Δex4-9 (Bozdagi et al., 2010) and Δex4-7 mutations in mouse (Peca et al., 2011) are closest to patients with intragenic exon 1-9 deletion and splice mutation of intron 5 in SHANK3 (Bonaglia et al., 2011; Hamdan et al., 2011)”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationcitation
This suggests differences in effects of Shank3 on mGluR1/5 signaling over development.
“suggesting differences in effects of Shank3 on mGluR1/5 signaling over development”
Quote in the paperSubstantial claim - Interpretationreasoning
Some observed phenotypes may arise from isoform-specific effects on synaptic transmission.
“Since different mutations affect different isoforms of Shank3, some of the observed phenotypes may arise from isoform-specific effects on synaptic transmission.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Data support circuit defects mediated by glutamate receptors in Shank3 mutant mice that appear synapse- and mutation-specific.
“Collectively, these data support circuit defects mediated by glutamate receptors in Shank3 mutant mice that appear to be both synapse- and mutation-specific.”
Quote in the paperSubstantial claim - Interpretationcitation
The different degree of synaptic transmission defects in mice with specific Shank3 mutations supports an isoform-specific contribution to synaptic function.
“The different degree of synaptic transmission defects in mice with specific Shank3 mutations supports the notion of an isoform-specific contribution to synaptic function.”
Quote in the paperSubstantial claim - Interpretationreasoning
The Disc1 mutation may be a confounding factor for phenotypic analysis of Shank3 mutant mice.
“and this may present a confounding factor for phenotypic analysis.”
Quote in the paperSubstantial claim - Premisecitation
Hippocampal LTP is reduced at CA1 synapses of Δex4-9J−/− and Δex4-9B mice.
“Hippocampal LTP was reduced at CA1 synapses of Δex4-9J−/− and Δex4-9B but not examined in Δex11−/− and Δex13-16−/− animals”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning
Phenotypic heterogeneity in Shank3 mutant mice appears consistent with clinical heterogeneity of patients harboring SHANK3 mutations.
“but the phenotypic heterogeneity itself appears consistent with the clinical heterogeneity of patients harboring SHANK3 mutations.”
Quote in the paperSubstantial claim - Premisecitation
Acute knockdown of Shank3 in cultured neurons decreases mGluR-dependent plasticity.
“Moreover, acute knockdown of Shank3 in cultured neurons decreases mGluR-dependent plasticity (Verpelli et al., 2011)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Verpelli et al., 2011 source
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- Interpretationreasoning
Different severity of similar behaviors with different mutations may reflect Shank3 isoform-specific contributions to specific behaviors.
“Different severity of similar behaviors with different mutations may reflect Shank3 isoform-specific contributions to specific behaviors.”
Quote in the paperNot a substantial claim - Premisecitation
Presynaptic responses measured by paired pulse ratio and input/output curves are not altered at corticostriatal synapses in Δex13-16−/− or Δex4-7−/− mice.
“Presynaptic responses measured by paired pulse ratio and input/output curves were not altered at corticostriatal synapses in Δex13-16−/− or Δex4-7−/− mice (Peca et al., 2011).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Peca et al., 2011 source
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- Premisecitation
Variable performances were noted in different cohorts of Δe4-9B−/− mice.
“Variable performances were noted in different cohorts of Δe4-9B−/− mice (Yang et al., 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Yang et al., 2012 source
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- Premisecitation
Repetitive behaviors measured by increased self-grooming and behavioral inflexibility in reverse Morris water maze were observed in Δex4-9J−/− and Δex4-9B−/− mice.
“Repetitive behaviors measured by increased self-grooming in the home cage and behavioral inflexibility in the reverse Morris water maze were observed in Δex4-9J−/− (Wang et al., 2011) and Δex4-9B−/− mice”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
More marked increase in self-grooming and self-injurious behaviors was observed in Δex11−/− and Δex13-16−/− mice.
“A more marked increase in self-grooming and self-injurious behaviors was observed in Δex11−/− and Δex13-16−/− mice”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
Number, frequency, and duration of ultrasonic vocalizations are altered in a sex-specific manner in Δex4-9J−/− mice.
“The number, frequency, and duration of ultrasonic vocalizations were altered in a sex-specific manner in Δex4-9J−/− mice (Wang et al., 2011).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wang et al., 2011 source
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- Interpretationreasoning
None of the Shank3 mouse mutations are equivalent to SHANK3 mutations found in human ASD patients.
“In a strict sense, none of these Shank3 mouse mutations are equivalent to SHANK3 mutations found in human ASD patients.”
Quote in the paperSubstantial claim - Interpretationcitation
Reduced social interaction and affiliation behaviors are the most notable and consistent observation in Shank3 mutant mice.
“The most notable and consistent observation was reduced social interaction and affiliation behaviors using different testing methods”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationcitation
This suggests an alteration in the set-point for bidirectional Hebbian synaptic plasticity.
“suggesting an alteration in the set-point for bidirectional Hebbian synaptic plasticity (Cho and Bear, 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Cho and Bear, 2010
Not checked in the free run.
- Interpretationreasoning
Because of molecular and clinical heterogeneity in ASD, interpreting human data from heterogeneous patient populations is challenging.
“Because of the molecular and clinical heterogeneity documented in ASD, the challenge of interpreting any human data from heterogeneous patient populations is obvious.”
Quote in the paperSubstantial claim - Premisecitation
Few clinical tools are available to evaluate behavioral features quantitatively in humans that could guide basic neurobiological studies in model systems.
“In fact, there are few clinical tools available to evaluate behavioral features quantitatively in humans that could guide more basic neurobiological studies in model systems (Lord et al., 2001; Lord et al., 2000b; Lord et al., 1994).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
None of the various social and communication behaviors have been validated as robustly translatable from rodents to humans.
“However, to date none of the various social and communication behaviors have been validated as robustly translatable from rodents to humans (Silverman et al., 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Silverman et al., 2010 source
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- Interpretationreasoning
Analyses of Shanks mutant mice indicate that subtle differences in mutations within a given ASD risk gene can produce overlapping but non-identical cellular, synaptic, and behavioral phenotypes.
“Analyses of the Shanks mutant mice indicate that subtle differences in mutations within a given ASD risk gene can produce overlapping but non-identical cellular, synaptic, and behavioral phenotypes.”
Quote in the paperSubstantial claim - Premisereasoning
Most current mouse models do not carry the human mutations.
“the diverse and often non-congruent phenotypes in various Shank mutant mice highlight the fact that most of the current mouse models do not carry the human mutations.”
Quote in the paperSubstantial claim - Interpretationcitation
This may be due to high specialization and diverse strategies for ethologically relevant social behaviors in mammals, particularly primates.
“This may be due to the high degree of specialization and diverse strategies for ethologically relevant social behaviors in mammals, particularly primates (Bucan and Abel, 2002; Flint and Mott, 2008; Kas et al., 2007).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Bucan and Abel, 2002
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- cites Flint and Mott, 2008
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- cites Kas et al., 2007 source
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- Premisecitation
Interventions that improve cognitive performance, behaviors, or neuropathology in rodents have frequently not led to accelerated therapeutic development, notably in Alzheimer's disease.
“Interventions that improve cognitive performance, behaviors, or neuropathology in rodents have frequently not led to accelerated therapeutic development, most notably in Alzheimer’s disease where reports abound of cured mouse models despite repeated clinical failures (Cisse et al., 2011; Gandy and DeKosky, 2013; Malenka and Malinow, 2011; Vaillend et al., 2002).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Cisse et al., 2011 source
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- cites Gandy and DeKosky, 2013
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- cites Malenka and Malinow, 2011
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- Premisecitation
Whole genome sequencing has identified a list of candidate genes in ASD.
“Recently, whole genome sequencing technology has successfully identified a list of candidate genes in ASD (Bi et al., 2012; Chahrour et al., 2012; Iossifov et al., 2012; Neale et al., 2012; O’Roak et al., 2012a; Sanders et al., 2012)”
Quote in the paperNot a substantial claim0 of 3 sources checked
- May combine two claims. 69
- Classified as probably not a substantial claim. 26
- The quote only partly states this claim. 1
May combine two claims.
InterpretationreasoningConserved synaptic dysfunction and related behaviors in Shank mouse mutants may help dissect ASD pathophysiology, but they also reveal divergent phenotypes caused by different mutations in the same gene.
“Conserved features of synaptic dysfunction and corresponding behaviors in Shank mouse mutants may help dissect the pathophysiology of ASD, but also highlight divergent phenotypes that arise from different mutations in the same gene.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationGenetic risk contributes significantly to idiopathic ASD, but the specific genetic alterations remain unknown in most cases.
“Genetic risk contributes significantly to idiopathic ASD, but the specific genetic alterations remain elusive in the majority of cases (Abrahams and Geschwind, 2008; Folstein and Rosen-Sheidley, 2001; State, 2010b).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Abrahams and Geschwind, 2008 source
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- cites Folstein and Rosen-Sheidley, 2001
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- cites State, 2010b
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PremisereasoningDiagnostic evaluations for ASD were not conducted in most cases or were carried out using different evaluation protocols.
“Diagnostic evaluations for ASD were not conducted in the majority of cases or were carried out using different evaluation protocols.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThe available data strongly support the conclusion that molecular defects of SHANK3 can cause ASD but with variable presentations.
“Together, these data strongly support a conclusion that molecular defects of SHANK3 can cause ASD but with variable presentations.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationMany missense mutations have been identified in SHANK3, but their clinical relevance has not been determined.
“Many missense mutations have been identified in SHANK3 (Gauthier et al., 2009; Moessner et al., 2007; Schaaf et al., 2011), but their clinical relevance has not been determined.”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenGenes implicated in metachromatic leukodystrophy (ARSA), congenital disorders of glycosylation (ALG12), and spinocerebellar ataxia type 10 (ATXN10) map within the 22q13.3 region.
“For example, genes implicated in metachromatic leukodystrophy (ARSA), congenital disorders of glycosylation (ALG12), and spinocerebellar ataxia type 10 (ATXN10) are mapped within the 22q13.3 region.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductreasoningThe quality of clinical data in the reports varies and is often incomplete, so direct comparisons should be made cautiously.
“Importantly, the quality of clinical data varies and is often incomplete in these reports and thus direct comparisons should be made with caution.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationPoint mutations of SHANK2 and microdeletions of SHANK1 and SHANK2 have been found in patients with ASD and intellectual disability.
“More recently, point mutations of SHANK2 and microdeletions of SHANK1 and SHANK2 have been found in patients with ASD and intellectual disability (Figures 1B and 1C) (Berkel et al., 2010; Leblond et al., 2012; O’Roak et al., 2012b; Pinto et al., 2010; Sato et al., 2012).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationThe key clinical features of PMS are global developmental delay, hypotonia, absent or severely delayed language, autistic behaviors, and intellectual disability.
“The key clinical features associated with PMS are global developmental delay, hypotonia, absent or severely delayed language, autistic behaviors, and intellectual disability (Phelan, 2007).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Phelan, 2007
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InterpretationcitationSimilar copy number variants are found across many genomic loci in both ASD and schizophrenia.
“This observation is consistent with recent reports that similar copy number variants (CNVs) are found across many genomic loci in both ASD and schizophrenia (Cook and Scherer, 2008; Gejman et al., 2011; Moreno-De-Luca et al., 2010; Sanders et al., 2011).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
InterpretationreasoningCompared with SHANK3, the number of cases with SHANK2 mutations is small but convincing.
“Compared to SHANK3, the number of cases with SHANK2 mutations is small but convincing.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductreasoningBecause the number of ASD cases with two genetic hits including SHANK2 is small, the validity of the multiple hit model remains to be tested in additional cohorts or functional studies.
“Because the number of ASD cases with two genetic hits including SHANK2 is small, the validity of the model remains to be tested in additional patient cohorts or by functional studies.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationSHANK3 mutations were the first and remain the best characterized SHANK mutations in human ASD.
“Mutations of SHANK3 were the first (Durand et al., 2007) and remain the best characterized SHANK mutations in human ASD (Boccuto et al., 2012; Moessner et al., 2007).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHomer family members regulate diverse synaptic functions.
“Among the various Shank binding proteins, Homer family members have been shown to regulate diverse synaptic functions (Hayashi et al., 2009; Sala et al., 2001; Tu et al., 1999).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationWhen overexpressed in cultured mouse neurons, Shanks recruit GluA1 AMPA receptors and increase formation of new synapses.
“When overexpressed in cultured neurons from mice, Shanks recruit GluA1 AMPA receptors and increases the formation of new synapses (Roussignol et al., 2005).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Roussignol et al., 2005 source
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PremisecitationShank3 forms multimers via its C-terminal SAM domain and its PDZ domain.
“Shank3 forms multimers via its C terminal SAM domain (Boeckers et al., 2005; Hayashi et al., 2009; Naisbitt et al., 1999) as well as its PDZ domain (Iskenderian-Epps and Imperiali, 2010).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationIn cultured rat neurons, knockdown of Shank3 selectively reduces synaptic mGluR5 receptors and impairs mGluR5-dependent signaling and plasticity.
“In cultured rat neurons, knock-down of Shank3 selectively reduces synaptic mGluR5 receptor and impairs mGluR5-dependent signaling and plasticity (Verpelli et al., 2011).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Verpelli et al., 2011 source
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Premisenone givenShank/ProSAP family members, including Shank3, have five conserved protein domains: ANK, SH3, PDZ, a proline-rich region with homer- and cortactin-binding sites, and SAM.
“Shank/ProSAP family members including Shank3 have five conserved protein domains – an ankyrin repeat domain (ANK), Src homology 3 (SH3) domain, PSD-95/Discs large/ZO-1 (PDZ) domain, a proline-rich region containing homer- and cortactin-binding sites, and a sterile alpha motif (SAM) domain (Figure 2A).”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationThe SAM domain of Shank3 has a Zn2+ binding site important for Shank3 protein folding at the PSD and for synaptogenesis and synapse maturation in vitro.
“The SAM domain of Shank3 has a Zn2+ binding site that is important for Shank3 protein folding at the PSD as well as for synaptogenesis and synapse maturation in vitro (Baron et al., 2006; Grabrucker et al., 2011a).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Baron et al., 2006 source
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- cites Grabrucker et al., 2011a
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InterpretationreasoningDifferent SHANK mutations may act through different mechanisms to alter protein-protein interactions at the postsynaptic density and cause synaptic dysfunction that may underlie clinical presentations.
“Different SHANK mutations may thus act through different mechanisms to alter protein-protein interactions at the PSD and cause synaptic dysfunction that may underlie clinical presentations of disorder.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningShank3 shares a very similar protein domain structure with Shank1, suggesting that Shank3 participates in a similar protein network with Homer1.
“Shank3 shares very similar protein domain structure to Shank1, suggesting that Shank3 participates in a similar protein network with Homer1.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationMutation in the cortactin binding site of Shank3 results in longer spines with reduced spine head area.
“In contrast, mutation in the cortactin binding site results in longer spines with reduced spine head area (Roussignol et al., 2005).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Roussignol et al., 2005 source
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PremisecitationExcessive mGluR5 signaling has been implicated in fragile X syndrome, which has clinical overlap with 22q13.3 deletions.
“although excessive mGluR5 signaling has been implicated in fragile X syndrome (Krueger and Bear, 2011), which has clinical overlap with 22q13.3 deletions (Phelan, 2008).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Krueger and Bear, 2011
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- cites Phelan, 2008 source
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PremisecitationShank3 shares a similar protein domain structure but has a different expression pattern and subcellular localization than Shank1 and Shank2.
“Shank3 shares a similar protein domain structure but has a different expression pattern and subcellular localization than Shank1 and Shank2 (Bockers et al., 2004; Peca et al., 2011; Tao-Cheng et al., 2010).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
Premisenone givenThe large protein complex organized by Shanks performs functions at the postsynaptic membrane including actin-based cytoskeletal remodeling, synapse formation, AMPA receptor endocytosis, and regulation of synaptic transmission and plasticity.
“The large protein complex organized by Shanks performs a variety of functions at the postsynaptic membrane including actin-based cytoskeletal remodeling, synapse formation, AMPA receptor endocytosis, and regulation of synaptic transmission and plasticity (Table 2).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationShank family proteins are ubiquitinated in an activity-dependent manner in neurons.
“Biochemically, Shank family proteins are ubiquitinated in an activity-dependent manner in neurons (Ehlers, 2003).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ehlers, 2003 source
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PremisecitationMutation of the PDZ domain of Shank3 reduces dendritic spine formation, while mutation of ANK-SH3 domains leads to spines with normal length but reduced spine head area.
“For example, mutation of the PDZ domain of Shank3 results in a reduction in dendritic spine formation while mutation of ANK-SH3 domains leads to spines with normal length but reduced spine head area.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Roussignol et al., 2005 source
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PremisecitationExpression of Shank3 isoforms is cell type-specific and developmentally regulated.
“The expression of Shank3 isoforms is cell type-specific and developmentally regulated (Lim et al., 1999; Maunakea et al., 2010).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationMany known ASD genes, such as neuroligins and neurexins, display complex isoform-specific expression in brain, with different isoforms having distinct functions.
“Consistent with this notion, many known ASD genes, such as neuroligins and neurexins, display a complex pattern of isoform-specific expression in brain (Boucard et al., 2005; Sudhof, 2008), with different isoforms having very distinct functions (Chih et al., 2006).”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHomer1 and Shank1 form a mesh-like matrix thought to function as an organizing lattice for PSD proteins.
“Homer1 and Shank1 form a mesh-like matrix that is thought to function as an organizing lattice for PSD proteins (Hayashi et al., 2009).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hayashi et al., 2009 source
Not checked in the free run.
May combine two claims.
InterpretationreasoningThe intron 19 splicing mutation will disrupt most SHANK3 isoforms but leave SHANK3f and other short isoforms intact.
“The intron 19 splicing mutation will disrupt most isoforms but leave SHANK3f and other short isoforms intact.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationAlternative splicing of exons 19-20 and isoforms of SHANK2E, SHANK2A, and SHANK2B are conserved in mice, but the status of SHANK2C and other spliced exons has not been confirmed.
“The alternative splicing of exons 19-20 and isoforms of SHANK2E (Jiang, unpublished data), SHANK2A, and SHANK2B (Lim et al., 1999) were conserved in mice but the status of SHANK2C and other spliced exons has not been confirmed.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Lim et al., 1999 source
Not checked in the free run.
May combine two claims.
PremisecitationSmaller dendritic spines were observed, but the ultrastructure of the PSD is unaffected at CA1 synapses of Shank1−/− mice.
“Smaller dendritic spines were observed, but the ultrastructure of the PSD is unaffected at CA1 synapses of Shank1−/− mice.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hung et al., 2008 source
Not checked in the free run.
May combine two claims.
InterpretationreasoningDeletion of Shank2a exon 7 or exons 6-7 causes a frame shift immediately after exon 7.
“The deletion of exon 7 and exon 6-7 of Shank2a (exons 17 and exons 16-17 of predicted full length Shank2) resulted in a frame shift of the open reading frame immediately after exon 7.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationmEPSCs from CA1 hippocampal neurons are unaltered in Shank2 Δex6-7−/− mice but reduced in Shank2 Δex7−/− mice.
“mEPSCs recorded from CA1 hippocampal neurons were unaltered in Shank2 Δex6-7−/− mice, but reduced in Shank2 Δex7−/−.”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
InterpretationcitationAnalyses of Shank2 Δex7 and Δex6-7 mice show similarities and significant differences in protein composition, synaptic development/function, and behavior.
“Analyses of protein composition, synaptic development and function, and behaviors have revealed similarity but also significant differences between these two lines of Shank2 mutant mice”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationSpatial learning and memory is impaired in Shank2 Δex6-7−/− mice but normal in Shank2 Δex7−/− mice.
“Spatial learning and memory was impaired in Shank2 Δex6-7−/− but normal in Shank2 Δex7−/− mice.”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationThe NMDA/AMPA current ratio is reduced at CA1 synapses in Shank2 Δex6-7−/− mice but increased at the same synapses in Shank2 Δex7−/− mice.
“Interestingly, the ratio of NMDA/AMPA currents was reduced at CA1 synapses in Shank2 Δex6-7−/− mice but increased at the same synapses of Shank2 Δex7−/− mice.”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningBecause the transcript structure has not been fully worked out, the possibility that the Shank1 mutant is not a complete knockout cannot be ruled out.
“Because the transcript structure has not been fully worked out, the possibility that this is not a complete Shank1 knockout cannot be ruled out.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationIn Shank2 Δex7−/− mice, GluN1 and GluN2B NMDA receptors are increased in hippocampus, and GluN1, GluN2A, and GluA1 are increased in striatum.
“In Shank2 Δex7−/− mice, GluN1 and GluN2B NMDA-type glutamate receptors in hippocampus and GluN1, GluN2A, and GluA1 in striatum are increased (Schmeisser et al., 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Schmeisser et al., 2012 source
Not checked in the free run.
May combine two claims.
PremisecitationNMDA receptor-dependent LTP in hippocampal CA1 synapses is increased and LTD is unaffected in Shank2 Δex7−/− mice.
“NMDA receptor-dependent LTP in hippocampal CA1 synapses was increased and LTD was unaffected in Shank2 Δex7−/− mice.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Schmeisser et al., 2012 source
Not checked in the free run.
May combine two claims.
PremisecitationBaseline synaptic transmission is reduced in Shank2 Δex7−/− mice, while normal synaptic transmission is observed in Shank2 Δex6-7−/− mice.
“Whereas baseline synaptic transmission was reduced in Shank2 Δex7−/− mice (Schmeisser et al., 2012), normal synaptic transmission was observed in Shank2 Δex6-7−/− mice (Won et al., 2012).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationSHANK3 has five CpG islands across the gene, and these islands display brain-specific and cell type-specific DNA methylation.
“To add further complexity, SHANK3 has five CpG islands across the gene and these CpG islands display brain-specific and cell type-specific DNA methylation (Figure 1A) (Beri et al., 2007; Ching et al., 2005; Maunakea et al., 2010).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationBasal synaptic transmission was reduced, but LTP and LTD in CA1 hippocampus were unaffected in Shank1−/− mice.
“Basal synaptic transmission was reduced but long-term potentiation (LTP) and long-term depression (LTD) in CA1 hippocampus were unaffected (Hung et al., 2008).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hung et al., 2008 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSHANK2E is also expressed in brain tissues in humans.
“However, a recent report indicates that SHANK2E is also expressed in brain tissues in humans (Leblond et al., 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Leblond et al., 2012 source
Not checked in the free run.
May combine two claims.
PremisecitationD-cycloserine restored the NMDA/AMPA ratio and improved social interaction in the three-chamber assay in Shank2 Δex6-7−/− mice.
“Interestingly, treatment with D-cycloserine, a NMDA receptor agonist, restored the NMDA/AMPA ratio and improved social interaction in the three-chamber social interaction assay in Shank2 Δex6-7−/− mice (Won et al., 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Won et al., 2012 source
Not checked in the free run.
May combine two claims.
PremisecitationBoth Shank2 Δex6-7−/− and Δex7−/− mice show hyperactivity, impaired social interaction, altered ultrasonic vocalizations, and increased self-grooming.
“Behaviorally, hyperactivity, impaired social interaction, altered ultrasonic vocalizations, and increased self-grooming were observed in both Shank2 Δex6-7−/− and Shank2 Δex7−/− mice.”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationBehavioral analyses revealed subtle impairments in social interaction and communication as well as increased repetitive behaviors in Shank1 mutant mice.
“Behavioral analyses revealed subtle impairments in social interaction and communication as well as increased repetitive behaviors (Silverman et al., 2011; Wohr et al., 2011).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationBoth NMDA receptor-dependent LTP and LTD at CA1 synapses are reduced in Shank2 Δex6-7−/− mice.
“In contrast, both NMDA receptor-dependent LTP and LTD at CA1 synapses were reduced in Shank2 Δex6-7−/− mice.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Won et al., 2012 source
Not checked in the free run.
May combine two claims.
PremisecitationShank1 mutant mice with a deletion of exons 14-15 encoding the PDZ domain were first reported in 2007, and more extensive behavioral analyses were conducted subsequently.
“Shank1 mutant mice with a deletion of exons 14-15 encoding the PDZ domain were first reported in 2007 (Hung et al., 2008) (Figure 3C) and more extensive behavioral analyses were conducted subsequently (Silverman et al., 2011; Wohr et al., 2011).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims. The quote only partly states this claim.
PremisecitationCDPPB rescued the reduced NMDA/AMPA ratio, recovered defective LTP and LTD, reversed biochemical changes, and reversed impaired social interaction without affecting other behavioral impairments in Shank2 Δex6-7−/− mice.
“In addition, treatment with CDPPB, an mGluR5-selective positive allosteric modulator, not only rescued the reduced NMDA/AMPA ratio but also recovered the defective LTP and LTD in hippocampus as well as biochemical changes in Shank2 Δex6-7−/− mice.”
- Also stated in: § Modeling SHANKs Mutations in Mice · plain
“CDPPB also reversed the impaired social interaction impairment in Shank2 Δex6-7−/− mice without affecting other behavioral impairments in these mice (Won et al., 2012).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Won et al., 2012 source
Not checked in the free run.
- Also stated in: § Modeling SHANKs Mutations in Mice · plain
May combine two claims.
InterpretationreasoningOverall, data support that synaptic function is impaired and social behaviors are abnormal in mice with Shank3 mutations.
“Overall, the data obtained from these studies support a general conclusion that synaptic function is impaired and social behaviors are abnormal in mice with Shank3 mutations.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationGluN2A and GluN2B are unchanged in striatum of Δex11−/− mice.
“but they were unchanged in the stratum of Δex11−/− mice (Schmeisser et al., 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Schmeisser et al., 2012 source
Not checked in the free run.
May combine two claims.
InterpretationcitationmRNAs joining exons 2-10 and 3-10 are stable and predicted to cause a frame shift shortly after exon 10.
“The mRNAs with joining of exons 2-10 and exons 3-10 were stable and were predicted to result in a frame shift in protein sequence shortly after exon 10.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationcitationΔex11 mutation is predicted to disrupt promoters 1 to 3 for Shank3a-c but not promoters 4 to 6 for Shank3d-f.
“The Δex11 mutation (Schmeisser et al., 2012) is predicted to disrupt promoters 1 to 3 for Shank3a-c but not promoters 4 to 6 for Shank3d-f”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Schmeisser et al., 2012 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningSuch variation may be due to isoform-specific effects of different mutations.
“Such variation may be due to isoform-specific effects of different mutations.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenDifferent brain regions including hippocampus, striatum, and neocortex were analyzed in different lines of mutant mice.
“Different brain regions including hippocampus, striatum, and neocortex were analyzed in different lines of mutant mice.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningAll these Shank3 deletions cause a frame shift in targeted transcripts, leading to truncated protein or disruption of full-length RNA/protein isoforms.
“Because all these deletions cause a frame shift for targeted transcripts, they all resulted in either a truncated Shank3 protein or possible disruption of full length RNA or protein isoforms due to the stability of encoded mRNA or protein.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationPSD thickness and length are not decreased in hippocampal CA1 synapses of ex4-9J−/− mice or Δex11−/− mice.
“but not in the hippocampal CA1 synapses in ex4-9J−/− mice (Wang et al., 2011) or Δex11−/− mice (Schmeisser et al., 2012).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationSpine density is decreased in striatum of Δex13-16−/− mice and in CA1 hippocampus of Δex4-9J−/− mice.
“spine density was decreased in the striatum and CA1 hippocampus of Δex13-16−/− and Δex4-9J−/− mice, respectively.”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenThe methods and techniques used in these analyses were similar but not identical.
“The methods and techniques used in these analyses were similar but not identical.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationThe reported Shank3 mutations include deletions of exons 4-9 (two designs), 4-7, 11, and 13-16.
“The mutations in these mice include deletions of exons 4-9 by two groups with slightly different design [(Δex4-9Buxbaum(B)) (Bozdagi et al., 2010) and Δex4-9Jiang (J) (Wang et al., 2011)], deletion of exons 4-7(Δex4-7) (Peca et al., 2011) encoding the ANK repeat domain, deletion of exon 11(Δex11) encoding the SH3 domain (Schmeisser et al., 2012), and deletion of exons 13-16 (Δex13-16) encoding the”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
InterpretationreasoningIn general, Shank3 mutation leads to loss of spines, reduced spine volume, and decreased PSD thickness in adult.
“In general, mutation of Shank3 leads to loss of spines, a reduction in spine volume, and decreased PSD thickness in the adult.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationSynaptic transmission is reduced at hippocampal CA1 synapses of Δex4-9B+/− and Δex4-9B−/− mice, but not in Δex4-9J−/− or Δex13-16−/− mice.
“synaptic transmission is reduced at hippocampal CA1 synapses of Δex4-9B+/− (Bozdagi et al., 2010) and Δex4-9B−/− (Yang et al., 2012), but not in Δex4-9J−/− (Wang et al., 2011) or Δex13-16−/− mice (Peca et al., 2011)”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationShort-term and long-term memory in a social transmission test are impaired in Δex4-9J−/− mice.
“Short-term and long-term memory in a social transmission test were impaired in Δex4-9J−/− mice (Wang et al., 2011).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wang et al., 2011 source
Not checked in the free run.
May combine two claims.
Premisenone givenIn human patients, ASD is a behavioral diagnosis with considerable clinical heterogeneity.
“In human patients, ASD is a behavioral diagnosis with considerable clinical heterogeneity.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationNMDA receptor-dependent LTD and mGluR-dependent LTD are not affected in CA1 hippocampus of ex4-9B mice.
“NMDA receptor-dependent long-term depression (LTD) induced by low frequency stimulus and mGluR-dependent LTD induced by PP-LFS were not affected in CA1 hippocampus of ex4-9B mice”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationIn striatum, mEPSC frequency and population spike amplitude are significantly decreased in Δex13-16−/− mice but only mildly affected in Δex4-7−/− mice.
“In striatum, the frequency of mEPSCs and amplitude of population spikes were significantly decreased in Δex13-16−/− mice, but only mildly affected in Δex4-7−/− mice (Peca et al., 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Peca et al., 2011 source
Not checked in the free run.
May combine two claims.
PremisecitationA naturally occurring Disc1 mutation in the 129 strain was segregated from the Δex4-9J−/− deletion but was not reported in other Shank3 mutant mice using 129 ES cells.
“A naturally occurring Disc1 (Disrupted in schizophrenia) mutation in the 129 strain of ES cells (Clapcote et al., 2007; Clapcote and Roder, 2006) was segregated from the Δex4-9J−/− deletion (Wang et al., 2011) but was not reported in other Shank3 mutant mice using mouse 129 ES cells (Peca et al., 2011; Schmeisser et al., 2012).”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationreasoningMouse genetic background, animal age, and specific protocols may contribute to variability in synaptic transmission results.
“In addition, mouse genetic background, animal age, and specific protocols used for the studies may contribute to the variability.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationreasoningThis variation may be due to differential spatial and temporal expression of other Shank family members or compositional variation across glutamatergic synapse populations.
“perhaps due to differential spatial and temporal expression of other Shank family members or to compositional variation across different populations of glutamatergic synapses.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningSynapse structure phenotypes vary with specific Shank3 mutations, differ across brain regions, and show developmental heterogeneity.
“Notably, synapse structure phenotypes vary with specific Shank3 mutations, are different in different brain regions, and display developmental heterogeneity”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationImpaired performance in Morris water maze is seen in Δex4-9J−/− mice but not in Δex13-16−/− and Δex4-9B−/− animals.
“Impaired performance in the Morris water maze task was seen in Δex4-9J−/− mice (Wang et al., 2011) but not in Δex13-16−/− (Peca et al., 2011) and Δex4-9B−/− animals (Yang et al., 2012).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
InterpretationreasoningAnalysis of heterozygotes versus homozygotes, different measurements in different brain regions, and different genetic backgrounds could all contribute to phenotypic heterogeneity.
“However, analysis of heterozygotes versus homozygotes, different measurements in different brain regions, as well as different genetic backgrounds could all contribute to phenotypic heterogeneity.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationMutations in SH3 and PDZ domains are missense in humans, whereas mouse Δex11 and Δex13-16 are exon deletion and frame shift mutations.
“Mutations in the SH3 and PDZ domains are missense mutations in humans (Boccuto et al., 2012; Waga et al., 2011), but mouse mutation of Δex11 and Δex13-16 are exon deletion and frame shift mutations (Peca et al., 2011; Schmeisser et al., 2012).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
InterpretationcitationShank3 mutant mice differ significantly in learning and memory task performance despite consistent intellectual disability in patients with multiple SHANK3 mutations.
“Despite the consistent intellectual disability reported in patients with multiple types of SHANK3 mutations, Shank3 mutant mice differed significantly in performance of learning and memory tasks.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationSeveral competing hypotheses have been proposed for core deficits and ancillary domains in ASD, but none have been widely accepted.
“Several competing hypotheses have been proposed to account for core deficits and ancillary symptomatic domains in ASD, but none have been widely accepted (Belmonte et al., 2004; Courchesne et al., 2007; Geschwind and Levitt, 2007; Rubenstein, 2010; Zoghbi, 2003).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisenone givenAlthough the triad of impaired social interaction, communication, and stereotypical behaviors is recognized as core to ASD, clinical presentation is highly varied in humans.
“Although the triad of impaired social interaction, communication, and stereotypical behaviors is recognized as core to ASD, the clinical presentation of these impairments is highly varied in humans.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationLittle is known about the neurological basis of ASD, and many brain regions and circuits have been implicated.
“Remarkably little is known about the neurological basis of ASD, and many brain regions and circuits have been implicated in ASD (Amaral et al., 2008; Anagnostou and Taylor, 2011; Bauman and Kemper, 2005; Courchesne et al., 2007).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningFunctional studies are critical to determine the pathogenicity of specific genetic variants.
“Functional studies are thus a critical component to determine the pathogenicity of specific genetic variants.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Premisenone givenBecause of the rarity of sequence variants across the population, establishing a causal role for specific variants in human disease has been challenging.
“Because of the rarity of sequence variants across the population, it has been challenge to establish a causal role for specific variants in human disease.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S2 (checkable). May combine two claims.
InterpretationreasoningSpecific mutations are likely to produce specific phenotypes in patients and must be modeled accordingly in mice for full translational potential.
“Specific mutations are likely to produce specific phenotypes in patients and hence must be modeled accordingly in mice for the mutant mice to have full translational potential.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn mouse behavioral studies, testing paradigms for learning and memory have been widely accepted.
“In mouse behavioral studies, testing paradigms for learning and memory have been widely accepted (Crawley, 2008; Crawley and Paylor, 1997; Morris, 1981).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningThe value of Shank mutant mice will depend critically on the ability to use human patients to validate their predictive utility.
“Ultimately, the value of Shank mutant mice will depend critically on the ability to use human patients to validate their predictive utility.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).
InterpretationreasoningThe lesson learned from modeling SHANK mutations in mice will be valuable to modeling other ASD candidate genes.
“The lesson learned from modeling SHANK mutations in mice will almost certainly be valuable to modeling other ASD candidate genes in the future.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Animal models can bridge human ASD genetics to circuit-based deficits and to therapeutic strategies.
“The development of animal models is an important step in bridging the human genetics of ASD to circuit-based deficits underlying the clinical presentation, and ultimately to discovering, designing, and deploying effective therapeutic strategies.”
The paper relies on this without support.
The rat Shank2 cDNA reference accurately predicts the exon numbering of full-length mouse Shank2.
“Using the longest rat cDNA of Shank2 deposited in GenBank (NM_201350) as a reference, one can deduce that exons 6 and 7 in mouse Shank2a isoform correspond to exons 16 and 17 of predicted full length mouse Shank2 deduced from rat cDNA (NM_201350)”
The paper relies on this without support.
Exons 6-7 of Shank2 encode the PDZ domain.
“Exons 6-7 encode the PDZ domain of Shank2.”
The paper relies on this without support.
Shank proteins regulate the abundance and signaling of ionotropic glutamate receptors at excitatory synapses.
“Shank proteins regulate the abundance and signaling of ionotropic glutamate receptors at excitatory synapses.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Translocation and breakpoint mutations in SHANK3 have been consistently implicated in developmental delays and ASD.
“Translocation and breakpoint mutations in SHANK3 have been consistently implicated in developmental delays and ASD [ 160 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [160]
Shank1-/- and Shank3B-/- mice display behavioral phenotypes with relevance to all core symptoms of ASD in humans.
“The two models display behavioral phenotypes with relevance to all core symptoms of ASD in humans [38–40]”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
The same mutation comparison uses two different identifiers
MinorThe comparison introduces p.E1311fs as one of three mutations, then discusses p.E1331fs in its place. The text does not establish that these are the same mutation.
“three cases with very similar mutations (p.A1227fs, p.E1311fs, and p.R1117X) in exon 21”
“Mutations p.A1227fs and p.E1331fs were found in patients with ASD or PDD-NOS, severe language delay, and significant intellectual disability”
Conflicting years for the first Shank1 mouse report
MinorThe introduction dates the first Shank1 mutant-mouse report to 2008, while the mouse-model section dates it to 2007. Both statements refer to the first report.
“Shank1 mutant mice were first reported in 2008 (Hung et al., 2008).”
“Shank1 mutant mice with a deletion of exons 14-15 encoding the PDZ domain were first reported in 2007 (Hung et al., 2008)”
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Synaptic Actin Dysregulation, a Convergent Mechanism of Mental Disorders?
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- Authors
- Jiang, Y.-H., & Ehlers, M. D.
- Affiliations
- Duke University (US)
- Pfizer (United States) (US)
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2013-04
- Volume
- 78
- Issue
- 1
- Pages
- 8-27
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC3659167
- OpenAlex
- W2014756302
- Cited by
- 488
- References
- 149
- Citations by year
- 2026: 12 · 2025: 35 · 2024: 32 · 2023: 38 · 2022: 44 · 2021: 39 · 2020: 40 · 2019: 33 · 2018: 45 · 2017: 42 · 2016: 49 · 2015: 42 · 2014: 28 · 2013: 9
- FWCI
- 5.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Autism Speaks
- Pfizer
- National Institute of Mental Health (R01MH098114)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (5K12-HD0043494-08, K12HD043494)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- autism spectrum disorder, Shank1, Shank2, SHANK3, synaptic scaffolding proteins, postsynaptic density, glutamatergic synapses, synaptic dysfunction, mouse models of autism, genetic mutations, phenotypic heterogeneity
- MeSH terms
- Animals, Autistic Disorder, Disease Models, Animal, Humans, Models, Molecular, Mutation, Nerve Tissue Proteins, Mice, Post-Synaptic Density
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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