https://academic.oup.com/brain/advance-article-abstract/doi/10.1093/brain/awz151/5519015?redirectedFrom=fulltext
https://www.ncbi.nlm.nih.gov/pubmed/31199454?dopt=Abstract
Mutations in C1orf194, encoding a calcium regulator, cause dominant Charcot-Marie-Tooth disease.
Mutations in C1orf194, encoding a calcium regulator, cause dominant Charcot-Marie-Tooth disease.
Brain. 2019 Jun 14;:
Authors: Sun SC, Ma D, Li MY, Zhang RX, Huang C, Huang HJ, Xie YZ, Wang ZJ, Liu J, Cai DC, Liu CX, Yang Q, Bao FX, Gong XL, Li JR, Hui Z, Wei XF, Zhong JM, Zhou WJ, Shang X, Zhang C, Liu XG, Tang BS, Xiong F, Xu XM
Abstract
Charcot-Marie-Tooth disease is a hereditary motor and sensory neuropathy exhibiting great clinical and genetic heterogeneity. Here, the identification of two heterozygous missense mutations in the C1orf194 gene at 1p21.2-p13.2 with Charcot-Marie-Tooth disease are reported. Specifically, the p.I122N mutation was the cause of an intermediate form of Charcot-Marie-Tooth disease, and the p.K28I missense mutation predominately led to the demyelinating form. Functional studies demonstrated that the p.K28I variant significantly reduced expression of the protein, but the p.I122N variant increased. In addition, the p.I122N mutant protein exhibited the aggregation in neuroblastoma cell lines and the patient’s peroneal nerve. Either gain-of-function or partial loss-of-function mutations to C1ORF194 can specify different causal mechanisms responsible for Charcot-Marie-Tooth disease with a wide range of clinical severity. Moreover, a knock-in mouse model confirmed that the C1orf194 missense mutation p.I121N led to impairments in motor and neuromuscular functions, and aberrant myelination and axonal phenotypes. The loss of normal C1ORF194 protein altered intracellular Ca2+ homeostasis and upregulated Ca2+ handling regulatory proteins. These findings describe a novel protein with vital functions in peripheral nervous systems and broaden the causes of Charcot-Marie-Tooth disease, which open new avenues for the diagnosis and treatment of related neuropathies.
PMID: 31199454 [PubMed – as supplied by publisher]
PubMed:31199454
Sun SC, Ma D, Li MY, Zhang RX, Huang C, Huang HJ, Xie YZ, Wang ZJ, Liu J, Cai DC, Liu CX, Yang Q, Bao FX, Gong XL, Li JR, Hui Z, Wei XF, Zhong JM, Zhou WJ, Shang X, Zhang C, Liu XG, Tang BS, Xiong F, Xu XM
