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A novel truncating variant p.(Arg297*) in the GRM1 gene causing autosomal-recessive cerebellar ataxia with juvenile-onset
Affiliation:1. Centre for Suicide Research, University of Oxford, Warneford Hospital, Oxford OX3 7JX, UK;2. Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, UK;3. Medical Sciences Division, University of Oxford, Warneford Hospital, Oxford OX3 7JX, UK;4. School of Pharmacy, University of Manchester, Manchester, UK;1. Department of Ophthalmology, Columbia University, New York, New York;2. Department of Pathology and Cell Biology, Columbia University, New York, New York;3. Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts;1. Pediatric Genetics Clinic, Schneider Children''s Medical Center of Israel, Petach Tikva 4920235, Israel;2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel;3. Pediatric Epilepsy Unit, Neurological Institute, Schneider Children''s Medical Center of Israel, Petach Tikva 4920235, Israel;4. Neurogenetic Service, Neurological Institute, Schneider Children''s Medical Center of Israel, Petach Tikva 4920235, Israel;5. Raphael Recanati Genetics Institute, Rabin Medical Center- Beilinson Hospital, Petach Tikva 4941492, Israel;6. Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan 5290002, Israel;7. Laboratory of Molecular Medicine, Rambam Health Care Campus, Haifa 3109601, Israel;8. Genomic Research Department, Emedgene Technologies, Tel Aviv, Israel;9. Department of Hematology-Oncology, Schneider Children''s Medical Center of Israel, Petach Tikva 4920235, Israel;10. Felsenstein Medical Research Center, Rabin Medical Center, Petach Tikva 4941492, Israel;11. Department of Pediatrics B, Schneider Children''s Medical Center of Israel, Petach Tikva 4920235, Israel
Abstract:
GRM1 gene, that is located on 6q24.3, encodes the metabotropic glutamate receptor type 1 (mGluR1), a transmembrane protein highly expressed in cerebellar Purkinje cells. Pathogenic variants in GRM1 have been reported only three times in humans, causing autosomal-recessive cerebellar ataxia with early-onset and intellectual disability or dominant forms of cerebellar ataxia with less severe phenotype in adults. We report a six-year-old boy, born to inbred parents, with an early-onset cerebellar syndrome due to a homozygous autosomal-recessive GRM1 pathogenic variant. In addition to cerebellar ataxia, axial hypotonia and oculomotor signs, he showed a severe and global developmental delay with lack of walking and speech and slight facial dysmorphic features. Brain MRI, performed at 1 year and at 5 years, showed a slowly progressive cerebellar atrophy. A novel homozygous truncating variant in the second exon of GRM1 gene (c.889C>T, p.(Arg297*)), inherited from the heterozygous healthy parents, was found by exome sequencing. Our observation not only emphasizes the central role of mGluR1-mediated signaling in cerebellar function and neurodevelopment but also provides valuable insights into the early clinical signs of recessive ataxia due to GRM1 pathogenic variants that were not reported previously. The difficulties of clinical differential diagnosis between this disease and other forms of congenital ataxia and the unspecific cerebellar atrophy on MRI highlight the importance of large-scale genetic investigations.
Keywords:Cerebellar ataxia  Spinocerebellar ataxia autosomal recessive,13  Metabotropic glutamate receptor type 1  GRM1
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