TY - JOUR
T1 - A Novel Missense Mutation in ERCC8 Co-Segregates with Cerebellar Ataxia in a Consanguineous Pakistani Family
AU - Gauhar, Zeeshan
AU - Tejwani, Leon
AU - Abdullah, Uzma
AU - Saeed, Sadia
AU - Shafique, Shagufta
AU - Badshah, Mazhar
AU - Choi, Jungmin
AU - Dong, Weilai
AU - Nelson-Williams, Carol
AU - Lifton, Richard P.
AU - Lim, Janghoo
AU - Raja, Ghazala K.
N1 - Funding Information:
This research was supported by National Institutes of Health grants NS083706 (J.L.) and AG076154 (J.L.), and the Lo Graduate Fellowship for Excellence in Stem Cell Research (L.T.), the Gruber Science Fellowship (L.T.), and National Institutes of Health grants T32 NS041228 (L.T.) and T32 NS007224 (L.T.).
Publisher Copyright:
© 2022 by the authors.
PY - 2022/10
Y1 - 2022/10
N2 - 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.
AB - 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.
KW - ARCA
KW - ERCC8
KW - autosomal-recessive cerebellar ataxias
KW - cerebellum
UR - http://www.scopus.com/inward/record.url?scp=85139812124&partnerID=8YFLogxK
U2 - 10.3390/cells11193090
DO - 10.3390/cells11193090
M3 - Article
C2 - 36231052
AN - SCOPUS:85139812124
SN - 2073-4409
VL - 11
JO - Cells
JF - Cells
IS - 19
M1 - 3090
ER -