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

• Published in: International journal of molecular sciences Vol. 24; no. 2; p. 1551
• Main Authors: Protasova, Maria S, Andreeva, Tatiana V, Klyushnikov, Sergey A, Illarioshkin, Sergey N, Rogaev, Evgeny I
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 12.01.2023; MDPI
• Subjects: Amino acid substitution; Amino acids; Ataxia; Cerebellar ataxia; Cerebellar Ataxia - congenital; Cerebellar Ataxia - diagnosis; Cerebellar Ataxia - genetics; cerebellar hypoplasia; Cerebellum; Cognitive ability; Domains; early-onset ataxia; Gene expression; Genetic diversity; Genomes; Glutamic acid receptors (metabotropic); GRM1; GRM1 gene; Humans; Intellectual disabilities; Intellectual Disability - genetics; metabotropic glutamate receptor 1; mGluR1; Minority & ethnic groups; Missense mutation; Motor task performance; Mutation; Pedigree; Phenotypes; Proteins; Receptors, Metabotropic Glutamate - genetics; Russian language; Spinocerebellar ataxia; Spinocerebellar Degenerations - congenital; Spinocerebellar Degenerations - genetics; Synaptic plasticity; Synaptic transmission; Synaptogenesis; Topology; metabotropic glutamate receptor 1; mGluR1; cerebellar ataxia; cerebellar hypoplasia; early-onset ataxia; GRM1
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24021551

Metabotropic glutamate receptor 1 (mGluR1) plays a crucial role in slow excitatory postsynaptic conductance, synapse formation, synaptic plasticity, and motor control. The gene is expressed mainly in the brain, with the highest expression in the cerebellum. Mutations in the 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 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 gene to date. We demonstrated that multiple rare variants in the underlie a broad diversity of clinical neurological and behavioral phenotypes depending on the nature and protein topology of the mutation.