Autosomal-Recessive Congenital Cerebellar Ataxia Is Caused by Mutations in Metabotropic Glutamate Receptor 1

V. Guergueltcheva, Dimitar Azmanov, Dora Angelicheva, K.R. Smith, T. Chamova, Laura Florez, Michael Bynevelt, T. Nguyne, S. Cherninkova, V. Bojinova, A. Kaprelyan, L. Angelova, Bharti Morar, David Chandler, R. Kaneva, M. Bahlo, I. Tournev, Luba Kalaydjieva

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Abstract

[Truncated abstract] Autosomal-recessive congenital cerebellar ataxia was identified in Roma patients originating from a small subisolate with a known strong founder effect. Patients presented with global developmental delay, moderate to severe stance and gait ataxia, dysarthria, mild dysdiadochokinesia, dysmetria and tremors, intellectual deficit, and mild pyramidal signs. Brain imaging revealed progressive generalized cerebellar atrophy, and inferior vermian hypoplasia and/or a constitutionally small brain were observed in some patients. Exome sequencing, used for linkage analysis on extracted SNP genotypes and for mutation detection, identified two novel (i.e., not found in any database) variants located 7 bp apart within a unique 6q24 linkage region. Both mutations cosegregated with the disease in five affected families, in which all ten patients were homozygous. The mutated gene, GRM1, encodes metabotropic glutamate receptor mGluR1, which is highly expressed in cerebellar Purkinje cells and plays an important role in cerebellar development and synaptic plasticity. The two mutations affect a gene region critical for alternative splicing and the generation of receptor isoforms; they are a 3 bp exon 8 deletion and an intron 8 splicing mutation (c.2652_2654del and c.2660+2T>G, respectively [RefSeq accession number NM_000838.3]). The functional impact of the deletion is unclear and is overshadowed by the splicing defect. Although ataxia lymphoblastoid cell lines expressed GRM1 at levels comparable to those of control cells, the aberrant transcripts skipped exon 8 or ended in intron 8 and encoded various species of nonfunctional receptors either lacking the transmembrane domain and containing abnormal intracellular tails or completely missing the tail.... Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Original languageEnglish
Pages (from-to)553-564
JournalAmerican Journal of Human Genetics
Volume91
Issue number3
Early online date16 Aug 2012
DOIs
Publication statusPublished - 7 Sep 2012

Fingerprint

Cerebellar Ataxia
Mutation
Introns
Exons
Gait Ataxia
Roma
Founder Effect
Exome
Dysarthria
Metabotropic Glutamate Receptors
Neuronal Plasticity
Purkinje Cells
Alternative Splicing
Tremor
Ataxia
Neuroimaging
Genes
Atrophy
Single Nucleotide Polymorphism
Protein Isoforms

Cite this

Guergueltcheva, V. ; Azmanov, Dimitar ; Angelicheva, Dora ; Smith, K.R. ; Chamova, T. ; Florez, Laura ; Bynevelt, Michael ; Nguyne, T. ; Cherninkova, S. ; Bojinova, V. ; Kaprelyan, A. ; Angelova, L. ; Morar, Bharti ; Chandler, David ; Kaneva, R. ; Bahlo, M. ; Tournev, I. ; Kalaydjieva, Luba. / Autosomal-Recessive Congenital Cerebellar Ataxia Is Caused by Mutations in Metabotropic Glutamate Receptor 1. In: American Journal of Human Genetics. 2012 ; Vol. 91, No. 3. pp. 553-564.
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abstract = "[Truncated abstract] Autosomal-recessive congenital cerebellar ataxia was identified in Roma patients originating from a small subisolate with a known strong founder effect. Patients presented with global developmental delay, moderate to severe stance and gait ataxia, dysarthria, mild dysdiadochokinesia, dysmetria and tremors, intellectual deficit, and mild pyramidal signs. Brain imaging revealed progressive generalized cerebellar atrophy, and inferior vermian hypoplasia and/or a constitutionally small brain were observed in some patients. Exome sequencing, used for linkage analysis on extracted SNP genotypes and for mutation detection, identified two novel (i.e., not found in any database) variants located 7 bp apart within a unique 6q24 linkage region. Both mutations cosegregated with the disease in five affected families, in which all ten patients were homozygous. The mutated gene, GRM1, encodes metabotropic glutamate receptor mGluR1, which is highly expressed in cerebellar Purkinje cells and plays an important role in cerebellar development and synaptic plasticity. The two mutations affect a gene region critical for alternative splicing and the generation of receptor isoforms; they are a 3 bp exon 8 deletion and an intron 8 splicing mutation (c.2652_2654del and c.2660+2T>G, respectively [RefSeq accession number NM_000838.3]). The functional impact of the deletion is unclear and is overshadowed by the splicing defect. Although ataxia lymphoblastoid cell lines expressed GRM1 at levels comparable to those of control cells, the aberrant transcripts skipped exon 8 or ended in intron 8 and encoded various species of nonfunctional receptors either lacking the transmembrane domain and containing abnormal intracellular tails or completely missing the tail.... Copyright {\circledC} 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.",
author = "V. Guergueltcheva and Dimitar Azmanov and Dora Angelicheva and K.R. Smith and T. Chamova and Laura Florez and Michael Bynevelt and T. Nguyne and S. Cherninkova and V. Bojinova and A. Kaprelyan and L. Angelova and Bharti Morar and David Chandler and R. Kaneva and M. Bahlo and I. Tournev and Luba Kalaydjieva",
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Guergueltcheva, V, Azmanov, D, Angelicheva, D, Smith, KR, Chamova, T, Florez, L, Bynevelt, M, Nguyne, T, Cherninkova, S, Bojinova, V, Kaprelyan, A, Angelova, L, Morar, B, Chandler, D, Kaneva, R, Bahlo, M, Tournev, I & Kalaydjieva, L 2012, 'Autosomal-Recessive Congenital Cerebellar Ataxia Is Caused by Mutations in Metabotropic Glutamate Receptor 1' American Journal of Human Genetics, vol. 91, no. 3, pp. 553-564. https://doi.org/10.1016/j.ajhg.2012.07.019

Autosomal-Recessive Congenital Cerebellar Ataxia Is Caused by Mutations in Metabotropic Glutamate Receptor 1. / Guergueltcheva, V.; Azmanov, Dimitar; Angelicheva, Dora; Smith, K.R.; Chamova, T.; Florez, Laura; Bynevelt, Michael; Nguyne, T.; Cherninkova, S.; Bojinova, V.; Kaprelyan, A.; Angelova, L.; Morar, Bharti; Chandler, David; Kaneva, R.; Bahlo, M.; Tournev, I.; Kalaydjieva, Luba.

In: American Journal of Human Genetics, Vol. 91, No. 3, 07.09.2012, p. 553-564.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Autosomal-Recessive Congenital Cerebellar Ataxia Is Caused by Mutations in Metabotropic Glutamate Receptor 1

AU - Guergueltcheva, V.

AU - Azmanov, Dimitar

AU - Angelicheva, Dora

AU - Smith, K.R.

AU - Chamova, T.

AU - Florez, Laura

AU - Bynevelt, Michael

AU - Nguyne, T.

AU - Cherninkova, S.

AU - Bojinova, V.

AU - Kaprelyan, A.

AU - Angelova, L.

AU - Morar, Bharti

AU - Chandler, David

AU - Kaneva, R.

AU - Bahlo, M.

AU - Tournev, I.

AU - Kalaydjieva, Luba

PY - 2012/9/7

Y1 - 2012/9/7

N2 - [Truncated abstract] Autosomal-recessive congenital cerebellar ataxia was identified in Roma patients originating from a small subisolate with a known strong founder effect. Patients presented with global developmental delay, moderate to severe stance and gait ataxia, dysarthria, mild dysdiadochokinesia, dysmetria and tremors, intellectual deficit, and mild pyramidal signs. Brain imaging revealed progressive generalized cerebellar atrophy, and inferior vermian hypoplasia and/or a constitutionally small brain were observed in some patients. Exome sequencing, used for linkage analysis on extracted SNP genotypes and for mutation detection, identified two novel (i.e., not found in any database) variants located 7 bp apart within a unique 6q24 linkage region. Both mutations cosegregated with the disease in five affected families, in which all ten patients were homozygous. The mutated gene, GRM1, encodes metabotropic glutamate receptor mGluR1, which is highly expressed in cerebellar Purkinje cells and plays an important role in cerebellar development and synaptic plasticity. The two mutations affect a gene region critical for alternative splicing and the generation of receptor isoforms; they are a 3 bp exon 8 deletion and an intron 8 splicing mutation (c.2652_2654del and c.2660+2T>G, respectively [RefSeq accession number NM_000838.3]). The functional impact of the deletion is unclear and is overshadowed by the splicing defect. Although ataxia lymphoblastoid cell lines expressed GRM1 at levels comparable to those of control cells, the aberrant transcripts skipped exon 8 or ended in intron 8 and encoded various species of nonfunctional receptors either lacking the transmembrane domain and containing abnormal intracellular tails or completely missing the tail.... Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

AB - [Truncated abstract] Autosomal-recessive congenital cerebellar ataxia was identified in Roma patients originating from a small subisolate with a known strong founder effect. Patients presented with global developmental delay, moderate to severe stance and gait ataxia, dysarthria, mild dysdiadochokinesia, dysmetria and tremors, intellectual deficit, and mild pyramidal signs. Brain imaging revealed progressive generalized cerebellar atrophy, and inferior vermian hypoplasia and/or a constitutionally small brain were observed in some patients. Exome sequencing, used for linkage analysis on extracted SNP genotypes and for mutation detection, identified two novel (i.e., not found in any database) variants located 7 bp apart within a unique 6q24 linkage region. Both mutations cosegregated with the disease in five affected families, in which all ten patients were homozygous. The mutated gene, GRM1, encodes metabotropic glutamate receptor mGluR1, which is highly expressed in cerebellar Purkinje cells and plays an important role in cerebellar development and synaptic plasticity. The two mutations affect a gene region critical for alternative splicing and the generation of receptor isoforms; they are a 3 bp exon 8 deletion and an intron 8 splicing mutation (c.2652_2654del and c.2660+2T>G, respectively [RefSeq accession number NM_000838.3]). The functional impact of the deletion is unclear and is overshadowed by the splicing defect. Although ataxia lymphoblastoid cell lines expressed GRM1 at levels comparable to those of control cells, the aberrant transcripts skipped exon 8 or ended in intron 8 and encoded various species of nonfunctional receptors either lacking the transmembrane domain and containing abnormal intracellular tails or completely missing the tail.... Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

U2 - 10.1016/j.ajhg.2012.07.019

DO - 10.1016/j.ajhg.2012.07.019

M3 - Article

VL - 91

SP - 553

EP - 564

JO - The American Journal of Human Genetics

JF - The American Journal of Human Genetics

SN - 0002-9297

IS - 3

ER -