标题:Whole-Genome Linkage Analysis with Whole-Exome Sequencing Identifies a Novel Frameshift Variant in NEFH in a Chinese Family with Charcot-Marie-Tooth 2: A Novel Variant in NEFH for Charcot-Marie-Tooth 2
作者:Bian, Xianli; Lin, Pengfei; Li, Jiangxia; Long, Feng; Duan, Ruonan; Yuan, Qianqian; Li, Yan; Gao, Fei; Gao, Shang; Wei, Shijun; Li 更多
作者机构:[Bian, Xianli; Li, Jiangxia; Long, Feng; Duan, Ruonan; Yuan, Qianqian; Li, Yan; Gao, Fei; Gao, Shang; Wei, Shijun; Li, Xi; Sun, Wenjie; Gong, Yaoqin; 更多
通讯作者:Yan, CZ;Liu, QJ;Yan, CZ;Liu, QJ
通讯作者地址:[Yan, CZ; Liu, QJ]Shandong Univ, Sch Med, Dept Med Genet, Jinan 250012, Shandong, Peoples R China;[Yan, CZ]Shandong Univ, Qilu Hosp, Dept Neurol, Jina 更多
来源:NEURODEGENERATIVE DISEASES
出版年:2018
卷:18
期:2-3
页码:74-83
DOI:10.1159/000487754
关键词:Charcot-Marie-Tooth disease; Neurofilament heavy polypeptide gene;; Whole-genome linkage analysis; Whole-exome sequencing; Zebrafish model
摘要:Background:Charcot-Marie-Tooth disease (CMT) is the most common neurodegenerative disorder of the peripheral nervous system. More than 50 genes/loci were found associated with the disease. We found a family with autosomal-dominant CMT2. Objective: To reveal the pathogenic gene of the family and further investigate the function of the variant. Methods: DNA underwent whole-genome linkage analysis for all family members and whole-exome sequencing for 2 affected members. Neurofilament light polypeptide and wild-type or mutant neurofilament heavy polypeptide (NEFH) were co-transfected into SW13 (vim-) cells. The nefh-knockdown zebrafish model was produced by using morpholino antisense oligonucleotides. Results: We identified a novel insertion variant (c.3057insG) in NEFH in the family. The variant led to the loss of a stop codon and an extended 41 amino acids in the protein. Immunofluorescence results revealed that mutant NEFH disrupted the neurofilament network and induced aggregation of NEFH protein. Knockdown of nefh in zebrafish caused a slightly or severely curled tail. The motor ability of nefh-knockdown embryos was impaired or even absent, and the embryos showed developmental defects of axons in motor neurons. The abnormal phenotype and axonal developmental defects could be rescued by injection of human wild-type but not human mutant NEFH mRNA. Conclusions: We identified a novel stop loss variant in NEFH that is likely pathogenic for CMT2, and the results provide further evidence for the role of an aberrant assembly of neurofilament in CMT. (C) 2018 S. Karger AG, Basel
收录类别:SCIE
资源类型:期刊论文
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