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ATP1A1 mutations cause intermediate Charcot‐Marie‐Tooth disease
Author(s) -
He Jin,
Guo Lingling,
Lin Shan,
Chen Wenfeng,
Xu Guorong,
Cai Bin,
Xu Liuqing,
Hong Jingmei,
Qiu Liangliang,
Wang Ning,
Chen Wanjin
Publication year - 2019
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23886
Subject(s) - missense mutation , biology , exome sequencing , gene , loss function , mutation , atrophy , exon , exome , genetics , muscle atrophy , cancer research , bioinformatics , phenotype
Abstract Intermediate Charcot‐Marie‐Tooth (CMT) disease is a heterogeneous group of inherited neuropathies characterized by progressive muscle weakness and atrophy of the distal extremities, distal sensory loss. There were still a large proportion of causative genes for intermediate CMT failed to be identified. Here, using whole‐exome sequencing technique, we identified two novel missense mutations in ATP1A1 gene, c.620C>T (p.S207F) and c.2629G>A (p.G877S), in two Chinese CMT families. Further functional analysis revealed that these mutations led to the loss function of the ATP1A1 protein. The two mutations did not affect the levels of messenger RNA but possessed a damaging effect on ATP1A1 protein expression and they downregulated the protein levels of ATP1A1 by promoting its proteasome degradation. Taken together, we confirmed ATP1A1 as a novel causative gene for intermediate CMT.