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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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Gene expression correlation between CTNND2 and known autism genes(a) Plot of all autism genes significantly (positive and negative) correlated with CTNND2 in the developing human brain (microarray data from www.brainspan.org). (b) Pathway analysis of the autism genes positively correlated with delta catenin reveals significant enrichment of genes involved in chromatin modification and dendrite morphogenesis.
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Figure 5: Gene expression correlation between CTNND2 and known autism genes(a) Plot of all autism genes significantly (positive and negative) correlated with CTNND2 in the developing human brain (microarray data from www.brainspan.org). (b) Pathway analysis of the autism genes positively correlated with delta catenin reveals significant enrichment of genes involved in chromatin modification and dendrite morphogenesis.

Mentions: We searched the correlated genes for autism29 (https://gene.sfari.org/autdb/) and intellectual disability candidates (Supplementary Table S7). Of 529 autism genes, 71 (61 positively, 10 negatively) were significantly correlated with CTNND2, representing significant enrichment (P=2.83x10−6). Next, we examined the correlations between these 71 genes and CTNND2 (Figure 5a) to find an intimate relationship between CTNND2 and autism genes. To interrogate the function of the 61 positively correlated genes, we again performed pathway analyses (Figure 5b) to find significant enrichment of genes involved in dendrite morphogenesis (P=2.96x10−3; PDLIM5,MAP2,SHANK1,CDKL5,DLG4) as well in chromatin modification (P=2.96x10−3; HDAC3,HUWE1,CREBBP,EP300,YEATS2,EP400, ATXN7,HCFC1 ARID1B,NSD1).


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)

Gene expression correlation between CTNND2 and known autism genes(a) Plot of all autism genes significantly (positive and negative) correlated with CTNND2 in the developing human brain (microarray data from www.brainspan.org). (b) Pathway analysis of the autism genes positively correlated with delta catenin reveals significant enrichment of genes involved in chromatin modification and dendrite morphogenesis.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 5: Gene expression correlation between CTNND2 and known autism genes(a) Plot of all autism genes significantly (positive and negative) correlated with CTNND2 in the developing human brain (microarray data from www.brainspan.org). (b) Pathway analysis of the autism genes positively correlated with delta catenin reveals significant enrichment of genes involved in chromatin modification and dendrite morphogenesis.
Mentions: We searched the correlated genes for autism29 (https://gene.sfari.org/autdb/) and intellectual disability candidates (Supplementary Table S7). Of 529 autism genes, 71 (61 positively, 10 negatively) were significantly correlated with CTNND2, representing significant enrichment (P=2.83x10−6). Next, we examined the correlations between these 71 genes and CTNND2 (Figure 5a) to find an intimate relationship between CTNND2 and autism genes. To interrogate the function of the 61 positively correlated genes, we again performed pathway analyses (Figure 5b) to find significant enrichment of genes involved in dendrite morphogenesis (P=2.96x10−3; PDLIM5,MAP2,SHANK1,CDKL5,DLG4) as well in chromatin modification (P=2.96x10−3; HDAC3,HUWE1,CREBBP,EP300,YEATS2,EP400, ATXN7,HCFC1 ARID1B,NSD1).

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