Loss of δ-catenin function in severe autism

Turner, Tychele N.; Sharma, Kamal; Oh, Edwin C.; Liu, Yangfan P.; Collins, Ryan L.; Sosa, Maria X.; Auer, Dallas R.; Brand, Harrison; Sanders, Stephan; Moreno‐De‐Luca, Daniel; Pihur, Vasyl; Plona, Teri M.; Pike, Kristen; Soppet, Daniel; Smith, Michael W.; Cheung, Sau Wai; Martin, Christa Lese; State, Matthew W.; Talkowski, Michael E.; Cook, Edwin H.; Huganir, Richard L.; Katsanis, Nicholas; Chakravarti, Aravinda

doi:10.1038/nature14186

Cited by 148 publications

(179 citation statements)

References 55 publications

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“…This methodology may even be applied to genes that have not been previously implicated in ASD. For example, CTNND2 was recently implicated as a critical gene in autism based on studies of female-enriched multiplex families (Turner et al 2015) but was not found in any of the gene lists used for the current study. Its mouse ortholog has seven adjacent TBR1-bound regions and a low LoF burden.…”

Section: Tbr1 Regulates Autism Risk Genesmentioning

confidence: 80%

TBR1 regulates autism risk genes in the developing neocortex

et al. 2016

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Exome sequencing studies have identified multiple genes harboring de novo loss-of-function (LoF) variants in individuals with autism spectrum disorders (ASD), including TBR1, a master regulator of cortical development. We performed ChIPseq for TBR1 during mouse cortical neurogenesis and show that TBR1-bound regions are enriched adjacent to ASD genes. ASD genes were also enriched among genes that are differentially expressed in Tbr1 knockouts, which together with the ChIP-seq data, suggests direct transcriptional regulation. Of the nine ASD genes examined, seven were misexpressed in the cortices of Tbr1 knockout mice, including six with increased expression in the deep cortical layers. ASD genes with adjacent cortical TBR1 ChIP-seq peaks also showed unusually low levels of LoF mutations in a reference human population and among Icelanders. We then leveraged TBR1 binding to identify an appealing subset of candidate ASD genes. Our findings highlight a TBR1-regulated network of ASD genes in the developing neocortex that are relatively intolerant to LoF mutations, indicating that these genes may play critical roles in normal cortical development.

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Section: Tbr1 Regulates Autism Risk Genesmentioning

confidence: 80%

TBR1 regulates autism risk genes in the developing neocortex

et al. 2016

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“…25 Wnt signaling is a critical developmental pathway; the zebrafish is a tractable model in which to study Wnt output [26][27][28][29][30][31] and to interrogate alleles relevant to neurocognitive traits. 32 We tested several representative missense variants, including the female-specific de novo vari- was chosen as a negative control (rs375996245; MAF < 0.002).…”

mentioning

confidence: 99%

“…Our data also suggest that the genetic architecture of DDX3X-mediated pathology in males is different. All 7,9,23,24,26), a wide nasal bridge and/or bulbous nasal tip (e.g., individuals 11,13,15,16), narrow alae nasi and/or anteverted nostrils (e.g., individuals 2, 8,9,12,14,18,24,27,32,35), and hypertelorism (e.g., individuals 5,7,8,20,27). Informed consent was obtained for all 30 individuals shown.…”

mentioning

confidence: 99%

Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling

Blok

Madsen

Juusola³

et al. 2015

The American Journal of Human Genetics

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232

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Intellectual disability (ID) affects approximately 1%-3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%-3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3X variant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations.

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“…Small exonic deletions of CTNND2 have also been reported in individuals with low normal IQ and learning problems with or without autistic features or developmental delay [Asadollahi et al, 2014]. In addition, a recent study identified that deleterious variants in the CYFIP1, DLG1, PLXNA3, and CTNND2 genes are enriched in severely affected patients in female-enriched multiplex families (FEMFs) with severe autism and demonstrated the loss-of-function effect of CTNND2 in autism and neurodevelopment by in vivo and in vitro functional analyses [Turner et al, 2015].…”

Section: Discussionmentioning

confidence: 98%

“…Interestingly, PLXNA3, with enriched variants in FEMFs, encodes a receptor for SEMA5A [Turner et al, 2015], which is located distal to CTNND2 (Fig. 3).…”

Section: Discussionmentioning

confidence: 99%

Multigenerational autosomal dominant inheritance of 5p chromosomal deletions

Zhang

Willing

Grange

et al. 2015

American J of Med Genetics Pt A

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Deletion of the short arm of chromosome 5 (5p-) is associated with phenotypic features including a cat-like cry in infancy, dysmorphic facial features, microcephaly, and intellectual disability, and when encompassing a minimal critical region, may be defined as Cri-du-Chat syndrome (CdCS). Most 5p deletions are de novo in origin, and familial cases are often associated with translocation and inversion. Herein, we report three multigenerational families carrying 5p terminal deletions of different size transmitted in an autosomal dominant manner causing variable clinical findings. Terminal 5p deletions and the mode of inheritance were clinically characterized and molecularly analyzed by a combination of microarray and fluorescence in situ hybridization analyses. Shared phenotypic features documented in this cohort included neuropsychiatric findings, poor growth, and dysmorphic facial features. This study supports newly recognized effects of aberrant SEMA5A and CTNND2 dosage on severity of autistic and cognitive phenotypes. Comparative analysis of the breakpoints narrows the critical region for the cat-like cry down to an interval less than 1 Mb encompassing a candidate gene ICE1, which regulates small nuclear RNA transcription. This study also indicates that familial terminal 5p deletion is a rare presentation displaying intra- and inter-familial phenotypic variability, the latter of which may be attributed to size and gene content of the deletion. The observed intra-familial phenotypic heterogeneity suggests that additional modifying elements including genetic and environmental factors may have an impact on the clinical manifestations observed in 5p deletion carriers, and in time, further high resolution studies of 5p deletion breakpoints will continue to aid in defining genotype-phenotype correlations.

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Loss of δ-catenin function in severe autism

Cited by 148 publications

References 55 publications

TBR1 regulates autism risk genes in the developing neocortex

TBR1 regulates autism risk genes in the developing neocortex

Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling

Multigenerational autosomal dominant inheritance of 5p chromosomal deletions

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