{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T22:53:50Z","timestamp":1790376830029,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T00:00:00Z","timestamp":1763596800000},"content-version":"vor","delay-in-days":19,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T00:00:00Z","timestamp":1761955200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    North Sea\u2010Progressive Myoclonus Epilepsy (NS\u2010PME) is a progressive neurological disorder, initially only associated with the homozygous\n                    <jats:italic>GOSR2<\/jats:italic>\n                    founder mutation (c.430G&gt;T; p.Gly144Trp). Clinical symptoms include untreatable early\u2010onset ataxia, cortical myoclonus and epilepsy. Recently, the spectrum of\n                    <jats:italic>GOSR2<\/jats:italic>\n                    mutations and associated phenotypic variability has expanded. To improve care and to facilitate genotype\u2013phenotype predictions for NS\u2010PME patients, we systematically reviewed all reported\n                    <jats:italic>GOSR2<\/jats:italic>\n                    mutations, clinical phenotypes, and pathophysiological findings. A narrative review literature search was conducted in PubMed, EMBASE, and Web of Science (1985\u2014August 2024) using the keywords \u201cGOSR2\u201d, \u201cGS27 protein\u201d, \u201cBos1\u201d, and \u201cMembrin\u201d. Only studies in English and specifically studies on GOSR2 function, pathogenic variants, clinical manifestations, and potential therapies were included. A total of 42 patients with 11 different\n                    <jats:italic>GOSR2<\/jats:italic>\n                    mutations were identified. Three main phenotypes were observed: progressive myoclonus ataxia\/epilepsy (PMA\/PME), congenital muscular dystrophy, and hearing loss. Orthopedic abnormalities were frequently reported. Intercurrent infections or fever often led to a worsening of symptoms. Glycosylation defects were reported in several compound heterozygous\n                    <jats:italic>GOSR2<\/jats:italic>\n                    variants. Molecularly,\n                    <jats:italic>GOSR2<\/jats:italic>\n                    mutations result in (partial) loss of function of the GOSR2\/SNARE complex, with mutation severity and the involvement of specific isoforms contributing to phenotypic variability.\n                    <jats:italic>GOSR2<\/jats:italic>\n                    mutations lead to progressive neurological disorders, primarily characterized by myoclonus ataxia\/epilepsy, muscular dystrophy, and hearing loss. The genotypic background of NS\u2010PME has expanded with pathogenic biallelic GOSR2 variants beyond the original homozygous founder mutation. Understanding the clinical spectrum and molecular mechanisms of GOSR2\u2010related diseases may facilitate more targeted treatment strategies as well as better\u2010informed phenotype predictions.\n                  <\/jats:p>","DOI":"10.1002\/jimd.70115","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T08:09:36Z","timestamp":1763626176000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Genotypic and Phenotypic Spectrum of\n                    <scp>\n                      <i>GOSR2<\/i>\n                    <\/scp>\n                    Mutations: Clinical and Pathophysiological Insights"],"prefix":"10.1002","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5386-189X","authenticated-orcid":false,"given":"Sjoukje S.","family":"Polet","sequence":"first","affiliation":[{"name":"Expertise Centre for Movement Disorders, Department of Neurology, University Medical Centre Groningen University of Groningen  Groningen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth Z.","family":"Siegal","sequence":"additional","affiliation":[{"name":"Department of Metabolic Diseases, Wilhelmina Children's Hospital University Medical Center Utrecht  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9147-2406","authenticated-orcid":false,"given":"Sabine A.","family":"Fuchs","sequence":"additional","affiliation":[{"name":"Department of Metabolic Diseases, Wilhelmina Children's Hospital University Medical Center Utrecht  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina A. J.","family":"Tijssen","sequence":"additional","affiliation":[{"name":"Expertise Centre for Movement Disorders, Department of Neurology, University Medical Centre Groningen University of Groningen  Groningen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5609-1309","authenticated-orcid":false,"given":"Tom J.","family":"de Koning","sequence":"additional","affiliation":[{"name":"Expertise Centre for Movement Disorders, Department of Neurology, University Medical Centre Groningen University of Groningen  Groningen the Netherlands"},{"name":"Department of Genetics, University Medical Centre Groningen University of Groningen  Groningen the Netherlands"},{"name":"Pediatrics, Department of Clinical Sciences Lund University  Lund 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