Loss of δ-catenin function in severe autism.

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Turner, TN; Sharma, K; Oh, EC; Liu, YP; Collins, RL; Collins, RL; Sosa, MX; Auer, DR; Brand, H; Sanders, SJ; Moreno-De-Luca, D; Pihur, V; Plona, T; Pike, K; Soppet, DR; Smith, MW; Cheung, SW; Martin, CL; State, MW; Talkowski, ME; Cook, E; Huganir, R; Katsanis, N; Chakravarti, A

Published Date

  • April 2015

Published In

Volume / Issue

  • 520 / 7545

Start / End Page

  • 51 - 56

PubMed ID

  • 25807484

Electronic International Standard Serial Number (EISSN)

  • 1476-4687

International Standard Serial Number (ISSN)

  • 0028-0836

Digital Object Identifier (DOI)

  • 10.1038/nature14186

Language

  • eng