Loss of δ-catenin function in severe autism

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

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 languageEnglish (US)
Pages (from-to)51-56
Number of pages6
JournalNature
Volume520
Issue number7545
DOIs
StatePublished - Apr 2 2015

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Loss of δ-catenin function in severe autism'. Together they form a unique fingerprint.

Cite this