Vavilov Institute of General Genetics, Russian Academy of Sciences, 119991 Moscow, Russia.
Center for Genetics and Life Science, Department of Genetics, Sirius University of Science and Technology, 354340 Sochi, Russia.
Int J Mol Sci. 2023 Jan 12;24(2):1551. 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.
代谢型谷氨酸受体 1（mGluR1）在慢兴奋性突触后电流、突触形成、突触可塑性和运动控制中发挥着关键作用。该基因主要在大脑中表达，在小脑中有最高的表达。先前已知该基因的突变会导致常染色体隐性和常染色体显性遗传性小脑共济失调。在这项研究中，对来自阿塞拜疆血统的先天性小脑共济失调患者进行了外显子组测序，发现了该基因中的一个新的纯合错义突变。该突变导致编码跨膜域 7 的高度进化保守区域中 p.Thr824Arg 的纯合氨基酸取代，这对于配体结合和受体活性的调节至关重要。这是第一个在 mGluR1 的最后一个跨膜域中发现突变导致先天性常染色体隐性小脑共济失调而无明显智力障碍的报道。此外，我们总结了迄今为止已知的该基因中所有假定的致病性遗传变异。我们证明， 中的多种罕见变异根据突变的性质和蛋白质拓扑结构，导致广泛的临床神经和行为表型多样性。
