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Rare Synaptogenesis-Impairing Mutations in SLITRK5 Are Associated with Obsessive Compulsive Disorder

Obsessive compulsive disorder (OCD) is substantially heritable, but few molecular genetic risk factors have been identified. Knockout mice lacking SLIT and NTRK-Like Family, Member 5 (SLITRK5) display OCD-like phenotypes including serotonin reuptake inhibitor-sensitive pathologic grooming, and corti...

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Autores principales: Song, Minseok, Mathews, Carol A., Stewart, S. Evelyn, Shmelkov, Sergey V., Mezey, Jason G., Rodriguez-Flores, Juan L., Rasmussen, Steven A., Britton, Jennifer C., Oh, Yong-Seok, Walkup, John T., Lee, Francis S., Glatt, Charles E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5234816/
https://www.ncbi.nlm.nih.gov/pubmed/28085938
http://dx.doi.org/10.1371/journal.pone.0169994
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author Song, Minseok
Mathews, Carol A.
Stewart, S. Evelyn
Shmelkov, Sergey V.
Mezey, Jason G.
Rodriguez-Flores, Juan L.
Rasmussen, Steven A.
Britton, Jennifer C.
Oh, Yong-Seok
Walkup, John T.
Lee, Francis S.
Glatt, Charles E.
author_facet Song, Minseok
Mathews, Carol A.
Stewart, S. Evelyn
Shmelkov, Sergey V.
Mezey, Jason G.
Rodriguez-Flores, Juan L.
Rasmussen, Steven A.
Britton, Jennifer C.
Oh, Yong-Seok
Walkup, John T.
Lee, Francis S.
Glatt, Charles E.
author_sort Song, Minseok
collection PubMed
description Obsessive compulsive disorder (OCD) is substantially heritable, but few molecular genetic risk factors have been identified. Knockout mice lacking SLIT and NTRK-Like Family, Member 5 (SLITRK5) display OCD-like phenotypes including serotonin reuptake inhibitor-sensitive pathologic grooming, and corticostriatal dysfunction. Thus, mutations that impair SLITRK5 function may contribute to the genetic risk for OCD. We re-sequenced the protein-coding sequence of the human SLITRK5 gene (SLITRK5) in three hundred and seventy seven OCD subjects and compared rare non-synonymous mutations (RNMs) in that sample with similar mutations in the 1000 Genomes database. We also performed in silico assessments and in vitro functional synaptogenesis assays on the Slitrk5 mutations identified. We identified four RNM’s among these OCD subjects. There were no significant differences in the prevalence or in silico effects of rare non-synonymous mutations in the OCD sample versus controls. Direct functional testing of recombinant SLITRK5 proteins found that all mutations identified in OCD subjects impaired synaptogenic activity whereas none of the pseudo-matched mutations identified in 1000 Genomes controls had significant effects on SLITRK5 function (Fisher’s exact test P = 0.028). These results demonstrate that rare functional mutations in SLITRK5 contribute to the genetic risk for OCD in human populations. They also highlight the importance of biological characterization of allelic effects in understanding genotype-phenotype relationships as there were no statistical differences in overall prevalence or bioinformatically predicted effects of OCD case versus control mutations. Finally, these results converge with others to highlight the role of aberrant synaptic function in corticostriatal neurons in the pathophysiology of OCD.
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spelling pubmed-52348162017-02-06 Rare Synaptogenesis-Impairing Mutations in SLITRK5 Are Associated with Obsessive Compulsive Disorder Song, Minseok Mathews, Carol A. Stewart, S. Evelyn Shmelkov, Sergey V. Mezey, Jason G. Rodriguez-Flores, Juan L. Rasmussen, Steven A. Britton, Jennifer C. Oh, Yong-Seok Walkup, John T. Lee, Francis S. Glatt, Charles E. PLoS One Research Article Obsessive compulsive disorder (OCD) is substantially heritable, but few molecular genetic risk factors have been identified. Knockout mice lacking SLIT and NTRK-Like Family, Member 5 (SLITRK5) display OCD-like phenotypes including serotonin reuptake inhibitor-sensitive pathologic grooming, and corticostriatal dysfunction. Thus, mutations that impair SLITRK5 function may contribute to the genetic risk for OCD. We re-sequenced the protein-coding sequence of the human SLITRK5 gene (SLITRK5) in three hundred and seventy seven OCD subjects and compared rare non-synonymous mutations (RNMs) in that sample with similar mutations in the 1000 Genomes database. We also performed in silico assessments and in vitro functional synaptogenesis assays on the Slitrk5 mutations identified. We identified four RNM’s among these OCD subjects. There were no significant differences in the prevalence or in silico effects of rare non-synonymous mutations in the OCD sample versus controls. Direct functional testing of recombinant SLITRK5 proteins found that all mutations identified in OCD subjects impaired synaptogenic activity whereas none of the pseudo-matched mutations identified in 1000 Genomes controls had significant effects on SLITRK5 function (Fisher’s exact test P = 0.028). These results demonstrate that rare functional mutations in SLITRK5 contribute to the genetic risk for OCD in human populations. They also highlight the importance of biological characterization of allelic effects in understanding genotype-phenotype relationships as there were no statistical differences in overall prevalence or bioinformatically predicted effects of OCD case versus control mutations. Finally, these results converge with others to highlight the role of aberrant synaptic function in corticostriatal neurons in the pathophysiology of OCD. Public Library of Science 2017-01-13 /pmc/articles/PMC5234816/ /pubmed/28085938 http://dx.doi.org/10.1371/journal.pone.0169994 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication.
spellingShingle Research Article
Song, Minseok
Mathews, Carol A.
Stewart, S. Evelyn
Shmelkov, Sergey V.
Mezey, Jason G.
Rodriguez-Flores, Juan L.
Rasmussen, Steven A.
Britton, Jennifer C.
Oh, Yong-Seok
Walkup, John T.
Lee, Francis S.
Glatt, Charles E.
Rare Synaptogenesis-Impairing Mutations in SLITRK5 Are Associated with Obsessive Compulsive Disorder
title Rare Synaptogenesis-Impairing Mutations in SLITRK5 Are Associated with Obsessive Compulsive Disorder
title_full Rare Synaptogenesis-Impairing Mutations in SLITRK5 Are Associated with Obsessive Compulsive Disorder
title_fullStr Rare Synaptogenesis-Impairing Mutations in SLITRK5 Are Associated with Obsessive Compulsive Disorder
title_full_unstemmed Rare Synaptogenesis-Impairing Mutations in SLITRK5 Are Associated with Obsessive Compulsive Disorder
title_short Rare Synaptogenesis-Impairing Mutations in SLITRK5 Are Associated with Obsessive Compulsive Disorder
title_sort rare synaptogenesis-impairing mutations in slitrk5 are associated with obsessive compulsive disorder
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5234816/
https://www.ncbi.nlm.nih.gov/pubmed/28085938
http://dx.doi.org/10.1371/journal.pone.0169994
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