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Genetic Variant in GRM1 Underlies Congenital Cerebellar Ataxia with No Obvious Intellectual Disability

Metabotropic glutamate receptor 1 (mGluR1) plays a crucial role in slow excitatory postsynaptic conductance, synapse formation, synaptic plasticity, and motor control. The GRM1 gene is expressed mainly in the brain, with the highest expression in the cerebellum. Mutations in the GRM1 gene have previ...

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Autores principales: Protasova, Maria S., Andreeva, Tatiana V., Klyushnikov, Sergey A., Illarioshkin, Sergey N., Rogaev, Evgeny I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9865416/
https://www.ncbi.nlm.nih.gov/pubmed/36675067
http://dx.doi.org/10.3390/ijms24021551
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author Protasova, Maria S.
Andreeva, Tatiana V.
Klyushnikov, Sergey A.
Illarioshkin, Sergey N.
Rogaev, Evgeny I.
author_facet Protasova, Maria S.
Andreeva, Tatiana V.
Klyushnikov, Sergey A.
Illarioshkin, Sergey N.
Rogaev, Evgeny I.
author_sort Protasova, Maria S.
collection PubMed
description Metabotropic glutamate receptor 1 (mGluR1) plays a crucial role in slow excitatory postsynaptic conductance, synapse formation, synaptic plasticity, and motor control. The GRM1 gene is expressed mainly in the brain, with the highest expression in the cerebellum. Mutations in the GRM1 gene have previously been known to cause autosomal recessive and autosomal dominant spinocerebellar ataxias. In this study, whole-exome sequencing of a patient from a family of Azerbaijani origin with a diagnosis of congenital cerebellar ataxia was performed, and a new homozygous missense mutation in the GRM1 gene was identified. The mutation leads to the homozygous amino acid substitution of p.Thr824Arg in an evolutionarily highly conserved region encoding the transmembrane domain 7, which is critical for ligand binding and modulating of receptor activity. This is the first report in which a mutation has been identified in the last transmembrane domain of the mGluR1, causing a congenital autosomal recessive form of cerebellar ataxia with no obvious intellectual disability. Additionally, we summarized all known presumable pathogenic genetic variants in the GRM1 gene to date. We demonstrated that multiple rare variants in the GRM1 underlie a broad diversity of clinical neurological and behavioral phenotypes depending on the nature and protein topology of the mutation.
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spelling pubmed-98654162023-01-22 Genetic Variant in GRM1 Underlies Congenital Cerebellar Ataxia with No Obvious Intellectual Disability Protasova, Maria S. Andreeva, Tatiana V. Klyushnikov, Sergey A. Illarioshkin, Sergey N. Rogaev, Evgeny I. Int J Mol Sci Article Metabotropic glutamate receptor 1 (mGluR1) plays a crucial role in slow excitatory postsynaptic conductance, synapse formation, synaptic plasticity, and motor control. The GRM1 gene is expressed mainly in the brain, with the highest expression in the cerebellum. Mutations in the GRM1 gene have previously been known to cause autosomal recessive and autosomal dominant spinocerebellar ataxias. In this study, whole-exome sequencing of a patient from a family of Azerbaijani origin with a diagnosis of congenital cerebellar ataxia was performed, and a new homozygous missense mutation in the GRM1 gene was identified. The mutation leads to the homozygous amino acid substitution of p.Thr824Arg in an evolutionarily highly conserved region encoding the transmembrane domain 7, which is critical for ligand binding and modulating of receptor activity. This is the first report in which a mutation has been identified in the last transmembrane domain of the mGluR1, causing a congenital autosomal recessive form of cerebellar ataxia with no obvious intellectual disability. Additionally, we summarized all known presumable pathogenic genetic variants in the GRM1 gene to date. We demonstrated that multiple rare variants in the GRM1 underlie a broad diversity of clinical neurological and behavioral phenotypes depending on the nature and protein topology of the mutation. MDPI 2023-01-12 /pmc/articles/PMC9865416/ /pubmed/36675067 http://dx.doi.org/10.3390/ijms24021551 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Protasova, Maria S.
Andreeva, Tatiana V.
Klyushnikov, Sergey A.
Illarioshkin, Sergey N.
Rogaev, Evgeny I.
Genetic Variant in GRM1 Underlies Congenital Cerebellar Ataxia with No Obvious Intellectual Disability
title Genetic Variant in GRM1 Underlies Congenital Cerebellar Ataxia with No Obvious Intellectual Disability
title_full Genetic Variant in GRM1 Underlies Congenital Cerebellar Ataxia with No Obvious Intellectual Disability
title_fullStr Genetic Variant in GRM1 Underlies Congenital Cerebellar Ataxia with No Obvious Intellectual Disability
title_full_unstemmed Genetic Variant in GRM1 Underlies Congenital Cerebellar Ataxia with No Obvious Intellectual Disability
title_short Genetic Variant in GRM1 Underlies Congenital Cerebellar Ataxia with No Obvious Intellectual Disability
title_sort genetic variant in grm1 underlies congenital cerebellar ataxia with no obvious intellectual disability
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9865416/
https://www.ncbi.nlm.nih.gov/pubmed/36675067
http://dx.doi.org/10.3390/ijms24021551
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