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A Novel Missense Mutation in ERCC8 Co-Segregates with Cerebellar Ataxia in a Consanguineous Pakistani Familyopen access

Authors
Gauhar, ZeeshanTejwani, LeonAbdullah, UzmaSaeed, SadiaShafique, ShaguftaBadshah, MazharChoi, JungminDong, WeilaiNelson-Williams, CarolLifton, Richard P.Lim, JanghooRaja, Ghazala K.
Issue Date
Oct-2022
Publisher
Multidisciplinary Digital Publishing Institute (MDPI)
Keywords
autosomal-recessive cerebellar ataxias; ARCA; cerebellum; ERCC8
Citation
Cells, v.11, no.19
Indexed
SCIE
SCOPUS
Journal Title
Cells
Volume
11
Number
19
URI
https://scholarworks.korea.ac.kr/kumedicine/handle/2021.sw.kumedicine/61655
DOI
10.3390/cells11193090
ISSN
2073-4409
2073-4409
Abstract
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>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.
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