Deleterious GRM1 mutations in schizophrenia.

We analysed a phenotypically well-characterised sample of 450 schziophrenia patients and 605 controls for rare non-synonymous single nucleotide polymorphisms (nsSNPs) in the GRM1 gene, their functional effects and family segregation. GRM1 encodes the metabotropic glutamate receptor 1 (mGluR1), whose...

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Autores principales:	Mohammed Akli Ayoub, Dora Angelicheva, David Vile, David Chandler, Bharti Morar, Juleen A Cavanaugh, Peter M Visscher, Assen Jablensky, Kevin D G Pfleger, Luba Kalaydjieva
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bcb99bb2a31f46f09b9bce709f1ef34a
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spelling	oai:doaj.org-article:bcb99bb2a31f46f09b9bce709f1ef34a2021-11-18T07:24:43ZDeleterious GRM1 mutations in schizophrenia.1932-620310.1371/journal.pone.0032849https://doaj.org/article/bcb99bb2a31f46f09b9bce709f1ef34a2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22448230/?tool=EBIhttps://doaj.org/toc/1932-6203We analysed a phenotypically well-characterised sample of 450 schziophrenia patients and 605 controls for rare non-synonymous single nucleotide polymorphisms (nsSNPs) in the GRM1 gene, their functional effects and family segregation. GRM1 encodes the metabotropic glutamate receptor 1 (mGluR1), whose documented role as a modulator of neuronal signalling and synaptic plasticity makes it a plausible schizophrenia candidate. In a recent study, this gene was shown to harbour a cluster of deleterious nsSNPs within a functionally important domain of the receptor, in patients with schizophrenia and bipolar disorder. Our Sanger sequencing of the GRM1 coding regions detected equal numbers of nsSNPs in cases and controls, however the two groups differed in terms of the potential effects of the variants on receptor function: 6/6 case-specific and only 1/6 control-specific nsSNPs were predicted to be deleterious. Our in-vitro experimental follow-up of the case-specific mutants showed that 4/6 led to significantly reduced inositol phosphate production, indicating impaired function of the major mGluR1 signalling pathway; 1/6 had reduced cell membrane expression; inconclusive results were obtained in 1/6. Family segregation analysis indicated that these deleterious nsSNPs were inherited. Interestingly, four of the families were affected by multiple neuropsychiatric conditions, not limited to schizophrenia, and the mutations were detected in relatives with schizophrenia, depression and anxiety, drug and alcohol dependence, and epilepsy. Our findings suggest a possible mGluR1 contribution to diverse psychiatric conditions, supporting the modulatory role of the receptor in such conditions as proposed previously on the basis of in vitro experiments and animal studies.Mohammed Akli AyoubDora AngelichevaDavid VileDavid ChandlerBharti MorarJuleen A CavanaughPeter M VisscherAssen JablenskyKevin D G PflegerLuba KalaydjievaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 3, p e32849 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mohammed Akli Ayoub Dora Angelicheva David Vile David Chandler Bharti Morar Juleen A Cavanaugh Peter M Visscher Assen Jablensky Kevin D G Pfleger Luba Kalaydjieva Deleterious GRM1 mutations in schizophrenia.
description	We analysed a phenotypically well-characterised sample of 450 schziophrenia patients and 605 controls for rare non-synonymous single nucleotide polymorphisms (nsSNPs) in the GRM1 gene, their functional effects and family segregation. GRM1 encodes the metabotropic glutamate receptor 1 (mGluR1), whose documented role as a modulator of neuronal signalling and synaptic plasticity makes it a plausible schizophrenia candidate. In a recent study, this gene was shown to harbour a cluster of deleterious nsSNPs within a functionally important domain of the receptor, in patients with schizophrenia and bipolar disorder. Our Sanger sequencing of the GRM1 coding regions detected equal numbers of nsSNPs in cases and controls, however the two groups differed in terms of the potential effects of the variants on receptor function: 6/6 case-specific and only 1/6 control-specific nsSNPs were predicted to be deleterious. Our in-vitro experimental follow-up of the case-specific mutants showed that 4/6 led to significantly reduced inositol phosphate production, indicating impaired function of the major mGluR1 signalling pathway; 1/6 had reduced cell membrane expression; inconclusive results were obtained in 1/6. Family segregation analysis indicated that these deleterious nsSNPs were inherited. Interestingly, four of the families were affected by multiple neuropsychiatric conditions, not limited to schizophrenia, and the mutations were detected in relatives with schizophrenia, depression and anxiety, drug and alcohol dependence, and epilepsy. Our findings suggest a possible mGluR1 contribution to diverse psychiatric conditions, supporting the modulatory role of the receptor in such conditions as proposed previously on the basis of in vitro experiments and animal studies.
format	article
author	Mohammed Akli Ayoub Dora Angelicheva David Vile David Chandler Bharti Morar Juleen A Cavanaugh Peter M Visscher Assen Jablensky Kevin D G Pfleger Luba Kalaydjieva
author_facet	Mohammed Akli Ayoub Dora Angelicheva David Vile David Chandler Bharti Morar Juleen A Cavanaugh Peter M Visscher Assen Jablensky Kevin D G Pfleger Luba Kalaydjieva
author_sort	Mohammed Akli Ayoub
title	Deleterious GRM1 mutations in schizophrenia.
title_short	Deleterious GRM1 mutations in schizophrenia.
title_full	Deleterious GRM1 mutations in schizophrenia.
title_fullStr	Deleterious GRM1 mutations in schizophrenia.
title_full_unstemmed	Deleterious GRM1 mutations in schizophrenia.
title_sort	deleterious grm1 mutations in schizophrenia.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/bcb99bb2a31f46f09b9bce709f1ef34a
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Deleterious GRM1 mutations in schizophrenia.

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