Abstract
Autism is a multifactorial neurodevelopmental disorder affecting more males than females; consequently, under a multifactorial genetic hypothesis, females are affected only when they cross a higher biological threshold. We hypothesize that deleterious variants at conserved residues are enriched in severely affected patients arising from female-enriched multiplex families with severe disease, enhancing the detection of key autism genes in modest numbers of cases. Here we show the use of this strategy by identifying missense and dosage sequence variants in the gene encoding the adhesive junction-associated δ-catenin protein (CTNND2) in female-enriched multiplex families and demonstrating their loss-of-function effect by functional analyses in zebrafish embryos and cultured hippocampal neurons from wild-type and Ctnnd2 null mouse embryos. Finally, through gene expression and network analyses, we highlight a critical role for CTNND2 in neuronal development and an intimate connection to chromatin biology. Our data contribute to the understanding of the genetic architecture of autism and suggest that genetic analyses of phenotypic extremes, such as female-enriched multiplex families, are of innate value in multifactorial disorders.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 51-56 |
| Number of pages | 6 |
| Journal | Nature |
| Volume | 520 |
| Issue number | 7545 |
| DOIs | |
| State | Published - Apr 2 2015 |
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Cite this
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 J.; Moreno-De-Luca, Daniel; Pihur, Vasyl; Plona, Teri; Pike, Kristen; Soppet, Daniel R.; Smith, Michael W.; Cheung, Sau Wai; Martin, Christa Lese; State, Matthew W.; Talkowski, Michael E.; Cook, Edwin; Huganir, Richard L; Katsanis, Nicholas; Chakravarti, Aravinda.
In: Nature, Vol. 520, No. 7545, 02.04.2015, p. 51-56.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Loss of δ-catenin function in severe autism
AU - Turner, Tychele N.
AU - Sharma, Kamal
AU - Oh, Edwin C.
AU - Liu, Yangfan P.
AU - Collins, Ryan L.
AU - Sosa, Maria X.
AU - Auer, Dallas R.
AU - Brand, Harrison
AU - Sanders, Stephan J.
AU - Moreno-De-Luca, Daniel
AU - Pihur, Vasyl
AU - Plona, Teri
AU - Pike, Kristen
AU - Soppet, Daniel R.
AU - Smith, Michael W.
AU - Cheung, Sau Wai
AU - Martin, Christa Lese
AU - State, Matthew W.
AU - Talkowski, Michael E.
AU - Cook, Edwin
AU - Huganir, Richard L
AU - Katsanis, Nicholas
AU - Chakravarti, Aravinda
PY - 2015/4/2
Y1 - 2015/4/2
N2 - Autism is a multifactorial neurodevelopmental disorder affecting more males than females; consequently, under a multifactorial genetic hypothesis, females are affected only when they cross a higher biological threshold. We hypothesize that deleterious variants at conserved residues are enriched in severely affected patients arising from female-enriched multiplex families with severe disease, enhancing the detection of key autism genes in modest numbers of cases. Here we show the use of this strategy by identifying missense and dosage sequence variants in the gene encoding the adhesive junction-associated δ-catenin protein (CTNND2) in female-enriched multiplex families and demonstrating their loss-of-function effect by functional analyses in zebrafish embryos and cultured hippocampal neurons from wild-type and Ctnnd2 null mouse embryos. Finally, through gene expression and network analyses, we highlight a critical role for CTNND2 in neuronal development and an intimate connection to chromatin biology. Our data contribute to the understanding of the genetic architecture of autism and suggest that genetic analyses of phenotypic extremes, such as female-enriched multiplex families, are of innate value in multifactorial disorders.
AB - Autism is a multifactorial neurodevelopmental disorder affecting more males than females; consequently, under a multifactorial genetic hypothesis, females are affected only when they cross a higher biological threshold. We hypothesize that deleterious variants at conserved residues are enriched in severely affected patients arising from female-enriched multiplex families with severe disease, enhancing the detection of key autism genes in modest numbers of cases. Here we show the use of this strategy by identifying missense and dosage sequence variants in the gene encoding the adhesive junction-associated δ-catenin protein (CTNND2) in female-enriched multiplex families and demonstrating their loss-of-function effect by functional analyses in zebrafish embryos and cultured hippocampal neurons from wild-type and Ctnnd2 null mouse embryos. Finally, through gene expression and network analyses, we highlight a critical role for CTNND2 in neuronal development and an intimate connection to chromatin biology. Our data contribute to the understanding of the genetic architecture of autism and suggest that genetic analyses of phenotypic extremes, such as female-enriched multiplex families, are of innate value in multifactorial disorders.
UR - http://www.scopus.com/inward/record.url?scp=84926357413&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84926357413&partnerID=8YFLogxK
U2 - 10.1038/nature14186
DO - 10.1038/nature14186
M3 - Article
C2 - 25807484
AN - SCOPUS:84926357413
VL - 520
SP - 51
EP - 56
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7545
ER -