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Cell Syst. 2015 Nov 25;1(5):361-374.

Identification of Human Neuronal Protein Complexes Reveals Biochemical Activities and Convergent Mechanisms of Action in Autism Spectrum Disorders.

Author information

1
Department of Genetics, Stanford Center for Genomics and Personalized Medicine, Stanford, California, 94305 USA.
2
Department of Biochemistry, Research and Innovation Centre, University of Regina, Regina, Saskatchewan S4S 0A2, Canada.
3
Department of Biochemistry, Research and Innovation Centre, University of Regina, Regina, Saskatchewan S4S 0A2, Canada; Banting and Best Department of Medical Research, Terrence Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada.
4
Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, California, 94305 USA; Department of Pediatrics, Stanford, California, 94305 USA.
5
Banting and Best Department of Medical Research, Terrence Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada.
6
Department of Genetics, Stanford Center for Genomics and Personalized Medicine, Stanford, California, 94305 USA; Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, California, 94305 USA.
7
Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, California, 94305 USA.

Abstract

The prevalence of autism spectrum disorders (ASDs) is rapidly growing, yet its molecular basis is poorly understood. We used a systems approach in which ASD candidate genes were mapped onto the ubiquitous human protein complexes and the resulting complexes were characterized. The studies revealed the role of histone deacetylases (HDAC1/2) in regulating the expression of ASD orthologs in the embryonic mouse brain. Proteome-wide screens for the co-complexed subunits with HDAC1 and six other key ASD proteins in neuronal cells revealed a protein interaction network, which displayed preferential expression in fetal brain development, exhibited increased deleterious mutations in ASD cases, and were strongly regulated by FMRP and MECP2 causal for Fragile X and Rett syndromes, respectively. Overall, our study reveals molecular components in ASD, suggests a shared mechanism between the syndromic and idiopathic forms of ASDs, and provides a systems framework for analyzing complex human diseases.

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