Format

Send to

Choose Destination
Nature. 2015 Apr 2;520(7545):51-6. doi: 10.1038/nature14186. Epub 2015 Mar 25.

Loss of δ-catenin function in severe autism.

Author information

1
1] Center for Complex Disease Genomics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Predoctoral Training Program in Human Genetics and Molecular Biology, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [3] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA.
2
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
3
Center for Human Disease Modeling, Duke University, Durham, North Carolina 27710, USA.
4
Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
5
1] Center for Complex Disease Genomics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA.
6
1] Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA [2] Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 USA.
7
1] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA [2] Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA.
8
1] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA [2] Department of Psychiatry, Yale University, New Haven, Connecticut 06511, USA.
9
Leidos Biomedical Research, Inc., Frederick, Maryland 21702, USA.
10
National Human Genome Research Institute, Bethesda, Maryland 20892, USA.
11
Baylor College of Medicine, Houston, Texas 77030, USA.
12
1] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA [2] Autism &Developmental Medicine Institute, Geisinger Health System, Lewisburg, Pennsylvania 17837, USA.
13
University of Illinois at Chicago, Chicago, Illinois 60608, USA.

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.

PMID:
25807484
PMCID:
PMC4383723
DOI:
10.1038/nature14186
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center