Journal Article

De novo mutations in schizophrenia implicate synaptic networks

Kavanagh, David H., Gormley, Padhraig, Williams, Hywel J., Banks, Eric, Scolnick, Edward M., Barker, Douglas D., Fromer, Menachem, Milanova, Vihra, Palta, Priit, Holmans, Peter, Johnson, Jessica S., Ruderfer, Douglas M., Humphreys, Isla, Rose, Samuel A., Grant, Seth G., Dwyer, Sarah, Carrera, Noa, Purcell, Shaun M., Chambert, Kimberly, Moran, Jennifer L., Roussos, Panos, Palotie, Aarno, Kirov, George, McCarroll, Steven A., Hannon, Eilis, Georgieva, Lyudmila, O’Donovan, Michael C., Mahajan, Milind, Rees, Elliott, Pocklington, Andrew J., Sklar, Pamela, Owen, Michael J.

2014

Overview

Inherited alleles account for most of the genetic risk for schizophrenia. However, new ( de novo ) mutations, in the form of large chromosomal copy number changes, occur in a small fraction of cases and disproportionally disrupt genes encoding postsynaptic proteins. Here we show that small de novo mutations, affecting one or a few nucleotides, are overrepresented among glutamatergic postsynaptic proteins comprising activity-regulated cytoskeleton-associated protein (ARC) and N -methyl- d -aspartate receptor (NMDAR) complexes. Mutations are additionally enriched in proteins that interact with these complexes to modulate synaptic strength, namely proteins regulating actin filament dynamics and those whose messenger RNAs are targets of fragile X mental retardation protein (FMRP). Genes affected by mutations in schizophrenia overlap those mutated in autism and intellectual disability, as do mutation-enriched synaptic pathways. Aligning our findings with a parallel case–control study, we demonstrate reproducible insights into aetiological mechanisms for schizophrenia and reveal pathophysiology shared with other neurodevelopmental disorders. The authors report the largest family-trio exome sequencing study of schizophrenia to date; mutations are overrepresented in genes for glutamatergic synaptic proteins and also genes mutated in autism and intellectual disability, providing insights into aetiological mechanisms and pathopshyisology shared with other neurodevelopmental disorders. Pathogenic mechanisms in schizophrenia Two major sequencing studies of the exome — the protein-coding portion of the genome — in schizophrenia sufferers and their relatives are published in this issue of Nature . Together they provide strong pointers to specific pathogenic mechanisms that disrupt the glutamatergic synapses in schizophrenia. In particular, mutations that influence the action of the scaffold protein ARC (activity-regulated cytoskeleton-associated protein) are prominently involved, as are mutations in targets of the fragile X mental retardation protein (FMRP). Defects in FMRP have previously been shown to be associated with autism spectrum disorders.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/514/2254 / 631/378/2583 / 692/499 / 692/699/476/1799 / Allelomorphism / Autism / Child Development Disorders, Pervasive - genetics / Cytoskeletal Proteins - metabolism / DNA sequencing / Exome - genetics / Fragile X Mental Retardation Protein - metabolism / Gene mutations / Genes / Genetic aspects / Health aspects / Humanities and Social Sciences / Humans / Intellectual Disability - genetics / Mental disorders / Models, Neurological / multidisciplinary / Mutation / Mutation - genetics / Mutation Rate / Nerve Net - metabolism / Nerve Net - physiopathology / Nerve Tissue Proteins - metabolism / Neural circuitry / Neural Pathways - metabolism / Neural Pathways - physiopathology / Nucleotide sequencing / Phenotype / Proteins / Psychological aspects / Receptors, N-Methyl-D-Aspartate - metabolism / Risk factors / RNA, Messenger - genetics / RNA, Messenger - metabolism / Schizophrenia / Schizophrenia - genetics / Schizophrenia - metabolism / Schizophrenia - physiopathology / Science / Studies / Substrate Specificity / Synapses / Synapses - metabolism