{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T03:20:33Z","timestamp":1764645633019,"version":"build-2065373602"},"reference-count":28,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,9,30]],"date-time":"2022-09-30T00:00:00Z","timestamp":1664496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NS083706","AG076154","T32 NS041228","T32 NS007224"],"award-info":[{"award-number":["NS083706","AG076154","T32 NS041228","T32 NS007224"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Lo Graduate Fellowship for Excellence in Stem Cell Research","award":["NS083706","AG076154","T32 NS041228","T32 NS007224"],"award-info":[{"award-number":["NS083706","AG076154","T32 NS041228","T32 NS007224"]}]},{"name":"Gruber Science Fellowship","award":["NS083706","AG076154","T32 NS041228","T32 NS007224"],"award-info":[{"award-number":["NS083706","AG076154","T32 NS041228","T32 NS007224"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Autosomal-recessive cerebellar ataxias (ARCAs) are heterogeneous rare disorders mainly affecting the cerebellum and manifest as movement disorders in children and young adults. To date, ARCA causing mutations have been identified in nearly 100 genes; however, they account for less than 50% of all cases. We studied a multiplex, consanguineous Pakistani family presenting with a slowly progressive gait ataxia, body imbalance, and dysarthria. Cerebellar atrophy was identified by magnetic resonance imaging of brain. Using whole exome sequencing, a novel homozygous missense mutation ERCC8:c.176T&gt;C (p.M59T) was identified that co-segregated with the disease. Previous studies have identified homozygous mutations in ERCC8 as causal for Cockayne Syndrome type A (CSA), a UV light-sensitive syndrome, and several ARCAs. ERCC8 plays critical roles in the nucleotide excision repair complex. The p.M59T, a substitution mutation, is located in a highly conserved WD1 beta-transducin repeat motif. In silico modeling showed that the structure of this protein is significantly affected by the p.M59T mutation, likely impairing complex formation and protein-protein interactions. In cultured cells, the p.M59T mutation significantly lowered protein stability compared to wildtype ERCC8 protein. These findings expand the role of ERCC8 mutations in ARCAs and indicate that ERCC8-related mutations should be considered in the differential diagnosis of ARCAs.<\/jats:p>","DOI":"10.3390\/cells11193090","type":"journal-article","created":{"date-parts":[[2022,10,8]],"date-time":"2022-10-08T01:52:21Z","timestamp":1665193941000},"page":"3090","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A Novel Missense Mutation in ERCC8 Co-Segregates with Cerebellar Ataxia in a Consanguineous Pakistani Family"],"prefix":"10.3390","volume":"11","author":[{"given":"Zeeshan","family":"Gauhar","sequence":"first","affiliation":[{"name":"University Institute of Biochemistry and Biotechnology (UIBB), Pir Mehr Ali Shah Arid Agriculture University Rawalpindi (PMAS-AAUR), Rawalpindi 46300, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3160-6270","authenticated-orcid":false,"given":"Leon","family":"Tejwani","sequence":"additional","affiliation":[{"name":"Interdepartmental Neuroscience Program, Yale School of Medicine, New Haven, CT 06510, USA"},{"name":"Department of Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7168-8266","authenticated-orcid":false,"given":"Uzma","family":"Abdullah","sequence":"additional","affiliation":[{"name":"University Institute of Biochemistry and Biotechnology (UIBB), Pir Mehr Ali Shah Arid Agriculture University Rawalpindi (PMAS-AAUR), Rawalpindi 46300, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6587-6543","authenticated-orcid":false,"given":"Sadia","family":"Saeed","sequence":"additional","affiliation":[{"name":"University Institute of Biochemistry and Biotechnology (UIBB), Pir Mehr Ali Shah Arid Agriculture University Rawalpindi (PMAS-AAUR), Rawalpindi 46300, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shagufta","family":"Shafique","sequence":"additional","affiliation":[{"name":"University Institute of Biochemistry and Biotechnology (UIBB), Pir Mehr Ali Shah Arid Agriculture University Rawalpindi (PMAS-AAUR), Rawalpindi 46300, Pakistan"},{"name":"Department of Health Informatics, Women University, Swabi 23430, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mazhar","family":"Badshah","sequence":"additional","affiliation":[{"name":"Department of Neurology, Pakistan Institute of Medical Sciences (PIMS), Islamabad 04485, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jungmin","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA"},{"name":"Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8376-1758","authenticated-orcid":false,"given":"Weilai","family":"Dong","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics and Genomics, Rockefeller University, New York, NY 10065, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carol","family":"Nelson-Williams","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard P.","family":"Lifton","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA"},{"name":"Laboratory of Human Genetics and Genomics, Rockefeller University, New York, NY 10065, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janghoo","family":"Lim","sequence":"additional","affiliation":[{"name":"Interdepartmental Neuroscience Program, Yale School of Medicine, New Haven, CT 06510, USA"},{"name":"Department of Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA"},{"name":"Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA"},{"name":"Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale School of Medicine, New Haven, CT 06510, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8362-7137","authenticated-orcid":false,"given":"Ghazala K.","family":"Raja","sequence":"additional","affiliation":[{"name":"University Institute of Biochemistry and Biotechnology (UIBB), Pir Mehr Ali Shah Arid Agriculture University Rawalpindi (PMAS-AAUR), Rawalpindi 46300, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1056\/NEJMra1006610","article-title":"The autosomal recessive cerebellar ataxias","volume":"366","author":"Anheim","year":"2012","journal-title":"N. 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