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Loss of δ-catenin function in severe autism.

Turner TN, Sharma K, Oh EC, Liu YP, 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 - Nature (2015)

Bottom Line: 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.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 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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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 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.

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Genetic features of a sex-dependent multifactorial model(a) Hypothetical sex-dependent liability distributions for autism under a multifactorial model of inheritance with a fixed biological threshold for affection. (b) Percent of Hirschsprung disease patients with damaging coding mutations within different risk classes characterized by gender, segment length, and familiality. The risk class is labeled 3,2,1,0 and is an additive score based on the number of factors with higher risk (female, long segment, multiplex) and comprise 13, 46, 60 and 55 patients, respectively (proportion trend test, P=3.1x10−6).
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Figure 1: Genetic features of a sex-dependent multifactorial model(a) Hypothetical sex-dependent liability distributions for autism under a multifactorial model of inheritance with a fixed biological threshold for affection. (b) Percent of Hirschsprung disease patients with damaging coding mutations within different risk classes characterized by gender, segment length, and familiality. The risk class is labeled 3,2,1,0 and is an additive score based on the number of factors with higher risk (female, long segment, multiplex) and comprise 13, 46, 60 and 55 patients, respectively (proportion trend test, P=3.1x10−6).

Mentions: The first genes discovered in autism were through syndromes (Supplementary Table S1), such as Rett and Fragile X syndromes3. Today, genomic analyses have definitively identified 12 genes, from an estimated 5004, with an excess of de novo or segregating mutations in typical isolated cases that are overwhelmingly male (Supplementary Table S1). Given such heterogeneity, it may be crucial to identify those genes whose mutations impart the greatest autism risk. Increased recurrence risk is associated with lower incidence (“Carter” effect), since any rare class must arise from higher genetic liability (Figure 1a)5. Consequently, gene discovery in epidemiologically rarer classes, namely, female gender, high phenotypic severity and familial cases, may be fruitful; this is further enhanced if we increase the genetic load by considering individuals who have all three features.


Loss of δ-catenin function in severe autism.

Turner TN, Sharma K, Oh EC, Liu YP, 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 - Nature (2015)

Genetic features of a sex-dependent multifactorial model(a) Hypothetical sex-dependent liability distributions for autism under a multifactorial model of inheritance with a fixed biological threshold for affection. (b) Percent of Hirschsprung disease patients with damaging coding mutations within different risk classes characterized by gender, segment length, and familiality. The risk class is labeled 3,2,1,0 and is an additive score based on the number of factors with higher risk (female, long segment, multiplex) and comprise 13, 46, 60 and 55 patients, respectively (proportion trend test, P=3.1x10−6).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383723&req=5

Figure 1: Genetic features of a sex-dependent multifactorial model(a) Hypothetical sex-dependent liability distributions for autism under a multifactorial model of inheritance with a fixed biological threshold for affection. (b) Percent of Hirschsprung disease patients with damaging coding mutations within different risk classes characterized by gender, segment length, and familiality. The risk class is labeled 3,2,1,0 and is an additive score based on the number of factors with higher risk (female, long segment, multiplex) and comprise 13, 46, 60 and 55 patients, respectively (proportion trend test, P=3.1x10−6).
Mentions: The first genes discovered in autism were through syndromes (Supplementary Table S1), such as Rett and Fragile X syndromes3. Today, genomic analyses have definitively identified 12 genes, from an estimated 5004, with an excess of de novo or segregating mutations in typical isolated cases that are overwhelmingly male (Supplementary Table S1). Given such heterogeneity, it may be crucial to identify those genes whose mutations impart the greatest autism risk. Increased recurrence risk is associated with lower incidence (“Carter” effect), since any rare class must arise from higher genetic liability (Figure 1a)5. Consequently, gene discovery in epidemiologically rarer classes, namely, female gender, high phenotypic severity and familial cases, may be fruitful; this is further enhanced if we increase the genetic load by considering individuals who have all three features.

Bottom Line: 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.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 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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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 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.

Show MeSH
Related in: MedlinePlus