The DOI matches its Crossref record; 113 of the 117 references it cites were found in a registry or an index; none of the 47 sources its claims cite is checked for support yet.
A Highly Conserved Program of Neuronal Microexons Is Misregulated in Autistic Brains
Open accessAbstract
Summary Alternative splicing (AS) generates vast transcriptomic and proteomic complexity. However, which of the myriad of detected AS events provide important biological functions is not well understood. Here, we define the largest program of functionally coordinated, neural-regulated AS described to date in mammals. Relative to all other types of AS within this program, 3-15 nucleotide ‘microexons’ display the most striking evolutionary conservation and switch-like regulation. These microexons modulate the function of interaction domains of proteins involved in neurogenesis. Most neural microexons are regulated by the neuronal-specific splicing factor nSR100/SRRM4, through its binding to adjacent intronic enhancer motifs. Neural microexons are frequently misregulated in the brains of individuals with autism spectrum disorder, and this misregulation is associated with reduced levels of nSR100. The results thus reveal a highly conserved program of dynamic microexon regulation associated with the remodeling of protein interaction networks during neurogenesis, the misregulation of which is linked to autism.
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TL;DR
This paper defines a large neural-regulated alternative splicing program in mammals, showing that 3–27 nucleotide microexons are exceptionally conserved, dynamically regulated during neuronal differentiation, and often controlled by nSR100/SRRM4. It further reports that microexons are frequently misregulated in autistic brains and that this misregulation correlates with reduced nSR100 expression.
Key findings
- Across human and mouse cell/tissue datasets, the authors identified about 2,500 neural-regulated AS events per species; microexons showed stronger neural-specific inclusion than longer exons (60.7% of microexons with ΔPSI>15 versus 9.5% of longer exons).
- Of 308 human neural-regulated microexons, 225 (73.5%) were also neural-differentially spliced in mouse, compared with 527 of 1,390 (37.9%) longer neural-regulated exons; many microexons were deeply conserved across vertebrates.
- During mouse ES-cell-to-cortical-neuron differentiation, 151 of 219 profiled neural-regulated microexons (69%) showed a PSI switch ≥50, and 65 (30%) showed a switch ≥90; nSR100 knockdown/overexpression affected more than half of profiled microexons.
- In ASD post-mortem superior temporal gyrus samples, 126 of 504 detected microexons (30%) had mean ΔPSI>10 between ASD and control, versus 825 of 15,405 longer exons (5.4%); nSR100 mRNA was downregulated on average by about 10% in ASD samples (p=0.014).
Methods
- The authors developed an RNA-Seq analysis pipeline to detect all AS classes, including microexons, and applied it to deep datasets from more than 50 human and mouse cell/tissue types, developmental stages, and several vertebrate species.
- They analyzed microexon regulation across six time points of mouse embryonic stem cell differentiation into cortical glutamatergic neurons, and used knockdown/overexpression plus PAR-iCLIP data to test nSR100/SRRM4 regulation.
- Protein interaction effects were tested with LUMIER assays and co-immunoprecipitation-western blotting for Apbb1 and AP1S2 microexons; ASD analyses used 24 autistic individuals and 24 matched controls, with 12 ASD samples showing the strongest ASD-associated expression signature and 12 controls selected for downstream comparisons.
Limitations
- The paper does not state a dedicated limitations section.
- Evident from the text: the ASD splicing analysis focused on a selected subset of 12 ASD and 12 control samples stratified by a pre-existing ASD gene-expression signature, so findings may not generalize to all autistic individuals.
- Evident from the text: the link between reduced nSR100 and microexon misregulation in ASD is correlational, and the authors do not establish causation; microexon detection also depends on a specialized pipeline and sufficient RNA-Seq read coverage.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here, we define the largest program of functionally coordinated, neural-regulated AS described to date in mammals.”
- Also stated in: § Global features of neural-regulated AS · plain
“These data reveal the largest program of neural-regulated AS events defined to date, and that this program is associated with a broader range of functional processes and pathways linked to nervous system biology than previously detected (Boutz et al., 2007; Fagnani et al., 2007; Ule et al., 2005).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Abstract
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In the paper
“Further analysis of the neural-regulated AS program revealed a striking inverse relationship between the length of an alternative exon and its propensity to be specifically included in neural tissues.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
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In the paper
“Nearly half of the neural-regulated AS events, including alternative retained introns, are predicted to generate protein isoforms both when the alternative sequence is included and skipped.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Global features of neural-regulated AS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, only ∼20% of AS events not subject to neural regulation (hereafter ‘non-neural’ events) have the potential to generate alternative protein isoforms (Figure 1B; p=2.7×10-248, proportion test).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Global features of neural-regulated AS
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In the paper
“By applying this pipeline to more than 50 diverse cell and tissue types each from human and mouse (Table S1), we identified ∼2,500 neural-regulated AS events in each species (Figure 1A and Table S2; Extended Experimental Procedures).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Global features of neural-regulated AS
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In the paper
“This trend extends to microexons as short as 3 nt.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
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In the paper
“Gene Ontology (GO) analysis shows that genes with neural-regulated AS events predicted to generate alternative protein isoforms form highly interconnected networks based on functions associated with neuronal biology, signaling pathways, structural components of the cytoskeleton and the plasma membrane (Figure 1C).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Global features of neural-regulated AS
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Neural microexons are frequently misregulated in the brains of individuals with autism spectrum disorder, and this misregulation is associated with reduced levels of nSR100.”
- Also stated in: § Microexons are misregulated in individuals with Autism Spectrum Disorder · plain
“These data reveal frequent misregulation of microexon splicing in the brain cortices of some individuals with ASD.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Microexons are misregulated in individuals with Autism Spectrum Disorder · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Relative to longer alternative exons, microexons, in particular those that are 3-15-nt long and neural-specifically included, are strongly enriched in multiple features indicative of functionally important AS.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
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In the paper
“the vast majority (>90%) of neural-regulated microexons display highest PSIs in neurons compared to all other cell and tissue types analyzed (Figure S2B-D, and Supplemental Information).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
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- It may state two separate claims as one. 28
- Probably not a substantial claim. 19
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Relative to all other types of AS within this program, 3-15 nucleotide ‘microexons’ display the most striking evolutionary conservation and switch-like regulation.”
- Also stated in: § Introduction · boosted
“Strikingly, neural-included microexons represent the most highly conserved and dynamically-regulated component of this program, and the corresponding genes are highly enriched in neuronal functions.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § Introduction · boosted
None of the sources cited for this claim have been checked yet.
In the paper
“Consistent with previous results (Fagnani et al., 2007; Pan et al., 2004), there is little overlap (8.5%) between genes with neural-regulated AS and mRNA expression, although these subsets of genes are highly enriched in overlapping GO terms (40% in common; Figure S1).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Global features of neural-regulated AS
What the sources say
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In the paper
“60.7% of alternative microexons show increased neural ‘percent spliced in’ (PSI) (ΔPSI>15) versus 9.5% of longer (average ∼135 nt) alternative exons (p=1.9×10-220, proportion test).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
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In the paper
“Supporting this view, among 49 available and de novo-modeled tertiary protein structures containing microexons, the corresponding residues are largely surface accessible amd unlikely to significantly affect the folding of the overlapping or adjacent protein domains (Figure S6A; Extended Experimental Procedures).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Distinct protein regulatory properties of microexons
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In the paper
“They are also significantly more often conserved at the levels of genomic sequence, detection in alternatively spliced transcripts, and neural-differential regulation (Figure 2D; Figure S2E, neural-regulated exons; p<0.001 for all pairwise comparisons, proportion tests.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
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In the paper
“Among several analyzed splicing regulators (Extended Experimental Procedures), knockdown and overexpression of nSR100 had the strongest effect on microexon regulation, with more than half of the profiled microexons displaying a pronounced change in inclusion level compared to controls (Figure 4A and S4A-S4H).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > The neural-specific splicing factor nSR100/SRRM4 regulates most neural microexons
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, proteins containing microexons are significantly more often central in protein-protein interaction networks and detected in protein complexes compared to proteins with other types of alternative exons (Figures 5H and S5O,P, p≤0.004 for all comparisons, Wilcoxon Rank Sum test).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons modulate the function of interaction domains
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Of 308 neural-regulated microexons in human, 225 (73.5%) are neural-differentially spliced in mouse, compared to only 527 of 1390 (37.9%) longer neural-regulated exons.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
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In the paper
“Despite the small number of genes representing clusters of kinetically-distinct sets of regulated microexons, each cluster revealed significant enrichment of specific GO terms including “regulation of GTPase activity” (Cluster I), “glutamate receptor binding” and “actin cytoskeleton organization” (Cluster V) (Table S4).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Dynamic regulation of microexons during neuronal differentiation
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Remarkably, while microexons represent only ∼1% of all AS events, they comprise approximately one third of all neural-regulated AS events conserved between human and mouse that are predicted to generate alternative protein isoforms (Figure S2F).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, microexon residues overlapping protein domains are significantly more often surface-accessible and enriched in charged residues (Figures 5C,D, and S5F-I; p<10-7 for all comparisons, proportion test) than are residues overlapping longer neural or non-neural exons.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Distinct protein regulatory properties of microexons
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In the paper
“Substitution of both microexon residues with alanine also enhanced the Kat5 interaction, although to a lesser extent than the presence of Arg and Glu (Figure 6C).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons modulate the function of interaction domains
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In the paper
“LUMIER and co-immunoprecipitation-western analysis reveals that inclusion of the microexon significantly enhances the interaction with Kat5, whereas there is little to no effect on the interaction with App (Figures 6C,D and Figure S6B,C).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons modulate the function of interaction domains
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In the paper
“These stages correspond to maturing post-mitotic neurons when pan-neuronal markers are already expressed, and are subsequent to the expression of most neurogenic transcription factors (Figure S3A).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Dynamic regulation of microexons during neuronal differentiation
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In the paper
“Remarkably, of 219 neural-regulated microexons with sufficient read coverage across time points, 151 (69%) displayed a PSI switch ≥ 50 between ES cells and mature neurons, and 65 (30%) a switch of ≥ 90 (Figure 3).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Dynamic regulation of microexons during neuronal differentiation
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In the paper
“Furthermore, comparable numbers of alternative microexons were detected in all analyzed vertebrate species, the majority of which are also strongly neural-specifically included (Figure 2E; Supplemental Information for details).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
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In the paper
“alternative microexons display the highest degrees of genomic sequence conservation, tissue-specific regulatory conservation, and frame-preservation potential, relative to all other classes of AS detected to date in vertebrate species”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
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In the paper
“Many of the corresponding genes act in common pathways and/or physically interact through protein-protein interactions (Figure 7F)”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The ASD and control brain samples analyzed are representative of the broader ASD and control populations.
None of the sources cited for this claim have been checked yet.
In the paper
“An important advance that is facilitating a more general understanding of the role of individual AS events is the observation that many cell/tissue type- and developmentally-regulated AS events are coordinately controlled by individual RBPs, and that these events are significantly enriched in genes that operate in common biological processes and pathways (Calarco et al., 2011; Irimia and Blencowe,”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Introduction
What the sources say
- Not checked yetcites Calarco et al., 2011 source
- Not checked yetcites Irimia and Blencowe, 2012
- Not checked yetcites Licatalosi and Darnell, 2010
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Alternative splicing (AS) – the process by which different pairs of splice sites are selected in precursor mRNA to generate multiple mRNA and protein products – is responsible for greatly expanding the functional and regulatory capacity of metazoan genomes (Braunschweig et al., 2013; Chen and Manley, 2009; Kalsotra and Cooper, 2011).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Introduction
What the sources say
- Not checked yetcites Braunschweig et al., 2013 source
- Not checked yetcites Chen and Manley, 2009
- Not checked yetcites Kalsotra and Cooper, 2011
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The results thus reveal a highly conserved program of dynamic microexon regulation associated with the remodeling of protein interaction networks during neurogenesis, the misregulation of which is linked to autism.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Abstract
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In the paper
“Indeed, among a set of analyzed neural-specific exons enriched in disordered regions, approximately one third promoted or disrupted interactions with partner proteins (Ellis et al., 2012).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Introduction
What the sources say
- Not checked yetcites Ellis et al., 2012 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“changes in the expression of the RBP RBFOX1 have been linked to misregulation of AS in the brains of individuals with autism spectrum disorder (ASD) (Voineagu et al., 2011).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Introduction
What the sources say
- Not checked yetcites Voineagu et al., 2011 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“These data reveal the largest program of neural-regulated AS events defined to date, and that this program is associated with a broader range of functional processes and pathways linked to nervous system biology than previously detected (Boutz et al., 2007; Fagnani et al., 2007; Ule et al., 2005).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Global features of neural-regulated AS
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Human disease mutations often disrupt cis-elements that control splicing and result in aberrant AS patterns (Cartegni et al., 2002).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Introduction
What the sources say
- Not checked yetcites Cartegni et al., 2002 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“However, the function of the vast majority of AS events detected to date are not known, and new landscapes of AS regulation remain to be discovered and characterized(Braunschweig et al., 2014; Eom et al., 2013).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Introduction
What the sources say
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Other disease changes affect the activity or expression of RBPs, causing entire programs of AS to be misregulated.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Introduction
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“While cell and tissue differentially-regulated AS events are significantly under-represented in functionally defined, folded domains in proteins, they are enriched in regions of protein disorder that typically are surface accessible and embed short linear interaction motifs (Buljan et al., 2012; Ellis et al., 2012; Romero et al., 2006).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Introduction
What the sources say
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Recently, we have shown that nSR100 promotes the inclusion of a subset of (longer) neural exons via binding to intronic UGC motifs proximal to suboptimal 3′ splice sites (Raj et al., 2014).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > The neural-specific splicing factor nSR100/SRRM4 regulates most neural microexons
What the sources say
- Not checked yetcites Raj et al., 2014 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Interestingly, mutations in AP1S2 have been previously implicated in phenotypic features associated with ASD and X-linked mental retardation (Borck et al., 2008; Tarpey et al., 2006).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons modulate the function of interaction domains
What the sources say
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The properties of microexons described above suggest that their misregulation could be associated with neurological disorders.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
- Rests on an assumption: Misregulation of alternative splicing frequently causes or contributes to human disease.
None of the sources cited for this claim have been checked yet.
In the paper
“The AP1 complex functions in the intracellular transport of cargo proteins between the trans-Golgi apparatus and endosomes by linking clathrin to the cargo proteins during vesicle membrane formation (Kirchhausen, 2000), and is important for the somatodendritic transport of proteins required for neuronal polarity (Farias et al., 2012).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons modulate the function of interaction domains
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
In the paper
“Apbb1 contains two phosphotyrosine binding domains, PTB1 and PTB2, which bind Kat5 and App, respectively (Cao and Sudhoff, 2001).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons modulate the function of interaction domains
What the sources say
- Not checked yetcites Cao and Sudhoff, 2001
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Sample selection was independent of any information on splicing changes.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Experimental Procedures > Comparison of ASD and control brain samples
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“an alternative microexon overlapping the SH3A domain of Intersectin 1 (Itsn1) has been reported to promote an interaction with Dynamin 1, and was proposed to modulate roles of Itsn1 in endocytosis, cell signaling and/or actin-cytoskeleton dynamics (Dergai et al., 2010)”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
What the sources say
- Not checked yetcites Dergai et al., 2010 source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The discovery and characterization of widespread, neural-regulated microexons in the present study thus enables a systematic investigation of new and highly conserved mechanisms controlling protein interaction networks associated with vertebrate nervous system development and neurological disorders.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“A neural-specific microexon in Protrudin/Zfyve27 was recently shown to increase its interaction with the vesicle-associated membrane protein-associated protein (VAP), and to promote neurite outgrowth (Ohnishi et al., 2014)”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
What the sources say
- Not checked yetcites Ohnishi et al., 2014 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“recent reports have begun to link individual microexons with neurodevelopmental disorders, including ASD (Zhu et al., 2014), schizophrenia (Ovadia and Shifman, 2011) and epilepsy (Rusconi et al., 2014)”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
What the sources say
- Not checked yetcites Zhu et al., 2014 source
- Not checked yetcites Ovadia and Shifman, 2011
- Not checked yetcites Rusconi et al., 2014
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“we have previously shown that nSR100 promotes neurite outgrowth (Calarco et al., 2009)”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
What the sources say
- Not checked yetcites Calarco et al., 2009 source
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Apbb1 is an adapter protein that functions in neurite outgrowth (Cheung et al., 2014; Ikin et al., 2007) and synaptic plasticity (Sabo et al., 2003), processes that have been linked to neurological disorders including ASD (Hussman et al., 2011)”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“the results suggest that the misregulation of microexons, as well as of longer alternative exons (Corominas et al., 2014; Voineagu et al., 2011), may impact protein interaction networks that are required for normal neuronal development and synaptic function”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The ASD and control brain samples analyzed are representative of the broader ASD and control populations.
The paper relies on this without support.
Misregulation of alternative splicing frequently causes or contributes to human disease.
“since the misregulation of AS frequently causes or contributes to human disease, there is a pressing need to systematically define the functions of splice variants in disease contexts.”
The paper relies on this without support.
Gene prediction algorithms, high-throughput RNA sequencing analysis methods, and RNA-Seq datasets generally lack the sensitivity and/or depth required to detect specific types of alternative splicing.
“Gene prediction algorithms, high-throughput RNA sequencing (RNA-Seq) analysis methods, and RNA-Seq datasets generally lack the sensitivity and/or depth required to detect specific types of AS.”
The paper relies on this without support.
It is generally not known which disease-misregulated alternative splicing events cause or contribute to disease phenotypes.
“As is the case with assessing the normal functions of AS, it is generally not known which disease-misregulated AS events cause or contribute to disease phenotypes.”
The paper relies on this without support.
Several genes with misregulated microexons have been linked to learning or intellectual disability.
“Other genes with misregulated microexons have been linked to learning or intellectual disability (e.g. APBB1, TRAPPC9, RAB3GAP1)”
The paper relies on this without support.
The ASD and control brain samples analyzed are representative of the broader ASD and control populations.
“We analyzed 24 autistic individuals and 24 controls matched by age and gender.”
The paper relies on this without support.
nSR100 mRNA expression levels reflect nSR100 protein activity or functional nSR100 levels.
“nSR100 mRNA expression is, on average, significantly downregulated in the brains of the analyzed ASD versus control subjects”
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?
In the citing paper
“the known positive correlation between SRRM4 and RBFOX1 and anticorrelation between PTBP1 and SRRM4 (refs 14,19)”
From Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism (2016) · cites this paper as [14]
In the citing paper
“Previous studies have identified alterations in local splicing events in ASD (19, 30) and in smaller cohorts in SCZ (2, 24) and BD (31).”
From Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018) · cites this paper as [30]
In the citing paper
“several studies have demonstrated that genes carrying microexons are preferentially expressed in brain and their splicing is dysregulated in ASD (30, 82, 83).”
From Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018) · cites this paper as [30]
In the citing paper
“nSR100 controls alternative splicing of 3–15 nucleotide “microexons,” which in turn alters protein-protein interactions, during neurogenesis. Reduced levels of nSR100 and dysregulated neuronal microexons are implicated in some cases of autism (Irimia et al., 2014).”
From Genetic Changes Shaping the Human Brain (2015) · cites this paper as Irimia et al., 2014
In the citing paper
“Recent studies have highlighted the importance of aberrant alternative splicing of mRNA in the brains of subjects with an ASD diagnosis (Corominas et al., 2014; Gandal et al., 2018; Irimia et al., 2014; Parikshak et al., 2016; Voineagu et al., 2011).”
From Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice (2019) · cites this paper as Irimia et al., 2014
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
ASD microexon misregulation rate is overstated
MajorThe stated count is 126 of 504 microexons, which is 25%, not 30%. This overstates a rate used to describe the extent of ASD-associated misregulation.
Reported 30 · recomputed 25
“126 of 504 (30%) detected alternative microexons display a mean ΔPSI > 10 between ASD and control subjects”
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Metadata
- Authors
- Irimia, M., Weatheritt, R. J., Ellis, J. D., Parikshak, N. N., Gonatopoulos-Pournatzis, T., Babor, M., Quesnel-Vallières, M., Tapial, J., Raj, B., O’Hanlon, D., Barrios-Rodiles, M., Sternberg, M. J. E., Cordes, S. P., Roth, F. P., Wrana, J. L., Geschwind, D. H., & Blencowe, B. J.
- Affiliations
- University of Toronto (CA)
- MRC Laboratory of Molecular Biology (GB)
- University of California, Los Angeles (US)
- Centre for Genomic Regulation (ES)
- Imperial College London (GB)
- Mount Sinai Hospital (CA)
- Canadian Institute for Advanced Research (CA)
- Corresponding author
- Irimia, Manuel
- Blencowe, Benjamin J.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-12
- Volume
- 159
- Issue
- 7
- Pages
- 1511-1523
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4390143
- OpenAlex
- W2139480055
- Semantic Scholar
- 50b56e7b67ca01c7c25009821818d9e4a479c378
- Cited by
- 693
- References
- 117
- Citations by year
- 2026: 59 · 2025: 63 · 2024: 64 · 2023: 62 · 2022: 59 · 2021: 87 · 2020: 69 · 2019: 49 · 2018: 56 · 2017: 47 · 2016: 40 · 2015: 32 · 2014: 4
- FWCI
- 16.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (5r01mh094714-04)
- Canadian Institutes of Health Research
- National Institute of Mental Health (5R01MH094714, R01-MH094714, F30MH099886, R37MH060233)
- National Human Genome Research Institute (U01HG001715, R01HG003224, P50HG004233)
- National Institute of General Medical Sciences (T32GM008042)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- microexons, alternative splicing, autism spectrum disorder, SRRM4, neurogenesis, protein-protein interaction domains, evolutionary conservation, brain transcriptome
- MeSH terms
- Animals, Child Development Disorders, Pervasive, Humans, Models, Molecular, Nerve Tissue Proteins, Neurons, Temporal Lobe, Alternative Splicing, Sequence Analysis, RNA, Mice, Protein Interaction Domains and Motifs, Neurogenesis
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.
A language model drew the claims from the paper on 2026-10-06, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-06 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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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