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 Cook, Richard Huganir, Nicholas Katsanis and Aravinda Chakravarti ()
Additional contact information
Tychele N. Turner: Center for Complex Disease Genomics, Johns Hopkins University School of Medicine
Kamal Sharma: Johns Hopkins University School of Medicine
Edwin C. Oh: Center for Human Disease Modeling, Duke University
Yangfan P. Liu: Center for Human Disease Modeling, Duke University
Ryan L. Collins: Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School
Maria X. Sosa: Center for Complex Disease Genomics, Johns Hopkins University School of Medicine
Dallas R. Auer: Center for Complex Disease Genomics, Johns Hopkins University School of Medicine
Harrison Brand: Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School
Stephan J. Sanders: National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles
Daniel Moreno- De-Luca: National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles
Vasyl Pihur: Center for Complex Disease Genomics, Johns Hopkins University School of Medicine
Teri Plona: Leidos Biomedical Research, Inc.
Kristen Pike: Leidos Biomedical Research, Inc.
Daniel R. Soppet: Leidos Biomedical Research, Inc.
Michael W. Smith: National Human Genome Research Institute
Sau Wai Cheung: Baylor College of Medicine
Christa Lese Martin: National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles
Matthew W. State: National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles
Michael E. Talkowski: Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School
Edwin Cook: University of Illinois at Chicago
Richard Huganir: Johns Hopkins University School of Medicine
Nicholas Katsanis: Center for Human Disease Modeling, Duke University
Aravinda Chakravarti: Center for Complex Disease Genomics, Johns Hopkins University School of Medicine

Nature, 2015, vol. 520, issue 7545, 51-56

Abstract: 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.

Date: 2015
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DOI: 10.1038/nature14186

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