{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T17:45:38Z","timestamp":1791049538436,"version":"4.1.0"},"reference-count":33,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,9,17]],"date-time":"2022-09-17T00:00:00Z","timestamp":1663372800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"South-Eastern Norway Regional Health Authority"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background and objectives: Autosomal recessive spinocerebellar ataxia-13 (SCAR13) is an ultra-rare disorder characterized by slowly progressive cerebellar ataxia, cognitive deficiencies, and skeletal and oculomotor abnormalities. The objective of this case report is to expand the clinical and molecular spectrum of SCAR13. Methods: We investigated a consanguineous Pakistani family with four patients partially presenting with clinical features of SCAR13 using whole exome sequencing. Segregation analysis was performed by Sanger sequencing in all the available individuals of the family. Results: Patients presented with quadrupedal gait, delayed developmental milestones, non-progressive peripheral neuropathy, and cognitive impairment. Whole exome sequencing identified a novel pathogenic nonsense homozygous variant, Gly240*, in the gene GRM1 as a cause of SCAR13 that segregates with the recessive disease. Discussion: We report a novel homozygous nonsense variant in the GRM1 gene in four Pakistani patients presenting with clinical features that partially overlap with the already reported phenotype of SCAR13. In addition, the family presented quadrupedal gait and non-progressive symptoms, manifestations which have not been recognized previously. So far, only four variants in GRM1 have been reported, in families of Roma, Iranian, and Tunisian origins. The current study adds to the mutation spectrum of GRM1 and provides a rare presentation of SCAR13, the first from the Pakistani population.<\/jats:p>","DOI":"10.3390\/genes13091667","type":"journal-article","created":{"date-parts":[[2022,9,18]],"date-time":"2022-09-18T23:39:22Z","timestamp":1663544362000},"page":"1667","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["A Novel Nonsense Variant in GRM1 Causes Autosomal Recessive Spinocerebellar Ataxia 13 in a Consanguineous Pakistani Family"],"prefix":"10.3390","volume":"13","author":[{"given":"Hammad","family":"Yousaf","sequence":"first","affiliation":[{"name":"Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering College (NIBGE-C), Pakistan Institute of Engineering and Applied Sciences (PIEAS), Islamabad 44000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ambrin","family":"Fatima","sequence":"additional","affiliation":[{"name":"Department of Biological and Biomedical Sciences, The Aga Khan University, Karachi 74800, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2389-3337","authenticated-orcid":false,"given":"Zafar","family":"Ali","sequence":"additional","affiliation":[{"name":"Centre for Biotechnology and Microbiology, University of Swat, Swat 01923, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahid M.","family":"Baig","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering College (NIBGE-C), Pakistan Institute of Engineering and Applied Sciences (PIEAS), Islamabad 44000, Pakistan"},{"name":"Department of Biological and Biomedical Sciences, The Aga Khan University, Karachi 74800, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"Toft","sequence":"additional","affiliation":[{"name":"Department of Neurology, Oslo University Hospital, P.O. Box 4950 Nydalen, N-0424 Oslo, Norway"},{"name":"Institute of Clinical Medicine, University of Oslo, P.O Box 1171, N-0318 Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6387-8019","authenticated-orcid":false,"given":"Zafar","family":"Iqbal","sequence":"additional","affiliation":[{"name":"Department of Neurology, Oslo University Hospital, P.O. Box 4950 Nydalen, N-0424 Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Chiang, P.I., Liao, T.W., and Chen, C.M. (2022). A Novel SETX Mutation in a Taiwanese Patient with Autosomal Recessive Cerebellar Ataxia Detected by Targeted Next-Generation Sequencing, and a Literature Review. Brain Sci., 12.","DOI":"10.3390\/brainsci12020173"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.nrl.2016.06.006","article-title":"Keys to overcoming the challenge of diagnosing autosomal recessive spinocerebellar ataxia","volume":"34","author":"Arias","year":"2019","journal-title":"Neurologia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/j.ajhg.2012.07.019","article-title":"Autosomal-recessive congenital cerebellar ataxia is caused by mutations in metabotropic glutamate receptor 1","volume":"91","author":"Guergueltcheva","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"103726","DOI":"10.1016\/j.ejmg.2019.103726","article-title":"A novel truncating variant p.(Arg297*) in the GRM1 gene causing autosomal-recessive cerebellar ataxia with juvenile-onset","volume":"62","author":"Cabet","year":"2019","journal-title":"Eur. J. Med. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Davarniya, B., Hu, H., Kahrizi, K., Musante, L., Fattahi, Z., Hosseini, M., Maqsoud, F., Farajollahi, R., Wienker, T.F., and Ropers, H.H. (2015). The role of a novel TRMT1 gene mutation and rare GRM1 gene defect in intellectual disability in two Azeri families. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0129631"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2173","DOI":"10.1098\/rstb.2008.2270","article-title":"Type-1 metabotropic glutamate receptor in cerebellar Purkinje cells: A key molecule responsible for long-term depression, endocannabinoid signalling and synapse elimination","volume":"363","author":"Kano","year":"2008","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1016\/j.neuropharm.2010.10.022","article-title":"Metabotropic glutamate receptors: From the workbench to the bedside","volume":"60","author":"Nicoletti","year":"2011","journal-title":"Neuropharmacology"},{"key":"ref_8","first-page":"648","article-title":"Cloning and expression of a human metabotropic glutamate receptor 1 alpha: Enhanced coupling on co-transfection with a glutamate transporter","volume":"48","author":"Desai","year":"1995","journal-title":"Mol. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"52","DOI":"10.3389\/fnmol.2012.00052","article-title":"Structure of metabotropic glutamate receptor C-terminal domains in contact with interacting proteins","volume":"5","author":"Enz","year":"2012","journal-title":"Front. Mol. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1126\/science.1249489","article-title":"Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator","volume":"344","author":"Wu","year":"2014","journal-title":"Science"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/0092-8674(94)90205-4","article-title":"Deficient cerebellar long-term depression and impaired motor learning in mGluR1 mutant mice","volume":"79","author":"Alba","year":"1994","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/B978-0-444-64189-2.00005-6","article-title":"Recessive ataxias","volume":"155","author":"Synofzik","year":"2018","journal-title":"Handb. Clin. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1212\/01.wnl.0000219042.60538.92","article-title":"Scale for the assessment and rating of ataxia: Development of a new clinical scale","volume":"66","author":"Baliko","year":"2006","journal-title":"Neurology"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Sambrook, J., and Russell, D.W. (2006). Purification of nucleic acids by extraction with phenol:chloroform. Cold Spring Harb. Protoc., 2006.","DOI":"10.1101\/pdb.prot4045"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows-Wheeler transform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The Sequence Alignment\/Map format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/ng.806","article-title":"A framework for variation discovery and genotyping using next-generation DNA sequencing data","volume":"43","author":"DePristo","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: Functional annotation of genetic variations from next-generation sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucl. Acids Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.1093\/bioinformatics\/btw046","article-title":"FILTUS: A desktop GUI for fast and efficient detection of disease-causing variants, including a novel autozygosity detector","volume":"32","author":"Vigeland","year":"2016","journal-title":"Bioinformatics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/ng.2892","article-title":"A general framework for estimating the relative pathogenicity of human genetic variants","volume":"46","author":"Kircher","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"D886","DOI":"10.1093\/nar\/gky1016","article-title":"CADD: Predicting the deleteriousness of variants throughout the human genome","volume":"47","author":"Rentzsch","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.neulet.2013.08.030","article-title":"Group I metabotropic glutamate receptors modulate late phase long-term potentiation in hippocampal CA1 pyramidal neurons: Comparison of apical and basal dendrites","volume":"553","author":"Fan","year":"2013","journal-title":"Neurosci. Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.ajhg.2017.08.005","article-title":"Dominant mutations in GRM1 cause spinocerebellar ataxia type 44","volume":"101","author":"Watson","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"ref_25","first-page":"1030","article-title":"MetaDome: Pathogenicity analysis of genetic variants through aggregation of homologous human protein domains","volume":"40","author":"Wiel","year":"2019","journal-title":"Hum. Mutat."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1007\/s13238-020-00808-5","article-title":"Structural insights into the activation initiation of full-length mGlu1","volume":"12","author":"Zhang","year":"2021","journal-title":"Protein Cell"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Kammermeier, P.J. (2006). Surface clustering of metabotropic glutamate receptor 1 induced by long Homer proteins. BMC Neurosci., 7.","DOI":"10.1186\/1471-2202-7-1"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"D836","DOI":"10.1093\/nar\/gkx1006","article-title":"Mouse Genome Database (MGD)-2018: Knowledgebase for the laboratory mouse","volume":"46","author":"Smith","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1124\/pr.108.000166","article-title":"Metabotropic glutamate 1 receptor: Current concepts and perspectives","volume":"60","author":"Ferraguti","year":"2008","journal-title":"Pharmacol. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1093\/cercor\/bhm193","article-title":"Involvement of the mGluR1 receptor in hippocampal synaptic plasticity and associative learning in behaving mice","volume":"18","author":"Fairen","year":"2008","journal-title":"Cereb. Cortex"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2179","DOI":"10.1093\/cercor\/bhs200","article-title":"Compensatory molecular and functional mechanisms in nervous system of the Grm1(crv4) mouse lacking the mGlu1 receptor: A model for motor coordination deficits","volume":"23","author":"Rossi","year":"2013","journal-title":"Cereb. Cortex"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1007\/s00415-009-5380-3","article-title":"The metabotropic glutamate receptor 1, GRM1: Evaluation as a candidate gene for inherited forms of cerebellar ataxia","volume":"257","author":"Rossi","year":"2010","journal-title":"J. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.nbd.2017.10.001","article-title":"Genetic inactivation of mGlu5 receptor improves motor coordination in the Grm1crv4 mouse model of SCAR13 ataxia","volume":"109","author":"Bossi","year":"2018","journal-title":"Neurobiol. 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