Tomaselli Pedro J, Rossor Alexander M, Horga Alejandro, Jaunmuktane Zane, Carr Aisling, Saveri Paola, Piscosquito Giuseppe, Pareyson Davide, Laura Matilde, Blake Julian C, Poh Roy, Polke James, Houlden Henry, Reilly Mary M
From the MRC Centre for Neuromuscular Diseases (P.J.T., A.M.R., A.H., A.C., M.L., M.M.R.), Department of Neuropathology (Z.J.), and Department of Neurogenetics (R.P., J.P., H.H.), National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK; Clinic of Central and Peripheral Degenerative Neuropathies Unit (P.S., G.P., D.P.), Department of Clinical Neurosciences, IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy; Department of Clinical Neurophysiology (J.C.B.), Norfolk and Norwich University Hospital, Norfolk, UK.
Neurology. 2017 Apr 11;88(15):1445-1453. doi: 10.1212/WNL.0000000000003819. Epub 2017 Mar 10.
To determine the prevalence and clinical and genetic characteristics of patients with X-linked Charcot-Marie-Tooth disease (CMT) due to mutations in noncoding regions of the gap junction β-1 gene ().
Mutations were identified by bidirectional Sanger sequence analysis of the 595 bases of the upstream promoter region, and 25 bases of the 3' untranslated region (UTR) sequence in patients in whom mutations in the coding region had been excluded. Clinical and neurophysiologic data were retrospectively collected.
Five mutations were detected in 25 individuals from 10 kindreds representing 11.4% of all cases of CMTX1 diagnosed in our neurogenetics laboratory between 1996 and 2016. Four pathogenic mutations, c.-17G>A, c.-17+1G>T, c.-103C>T, and c.-146-90_146-89insT were detected in the 5'UTR. A novel mutation, c.*15C>T, was detected in the 3' UTR of in 2 unrelated families with CMTX1 and is the first pathogenic mutation in the 3'UTR of any myelin-associated CMT gene. Mutations segregated with the phenotype, were at sites predicted to be pathogenic, and were not present in the normal population.
Mutations in noncoding DNA are a major cause of CMTX1 and highlight the importance of mutations in noncoding DNA in human disease. Next-generation sequencing platforms for use in inherited neuropathy should therefore include coverage of these regions.
确定由于缝隙连接β-1基因非编码区突变导致的X连锁型夏科-马里-图斯病（CMT）患者的患病率、临床及遗传特征。
对编码区突变已被排除的患者，通过对上游启动子区域595个碱基以及3'非翻译区（UTR）25个碱基进行双向桑格测序分析来鉴定突变。回顾性收集临床和神经生理学数据。
在1996年至2016年间于我们神经遗传学实验室诊断的所有CMTX1病例中，10个家系的25名个体检测到5种突变，占11.4%。在5'UTR中检测到4种致病突变，即c.-17G>A、c.-17+1G>T、c.-103C>T和c.-146-90_146-89insT。在2个无关的CMTX1家系中，在3'UTR检测到一种新的突变c.*15C>T，这是任何髓鞘相关CMT基因3'UTR中的首个致病突变。突变与表型共分离，位于预测为致病的位点，且在正常人群中不存在。
非编码DNA突变是CMTX1的主要病因，凸显了非编码DNA突变在人类疾病中的重要性。因此，用于遗传性神经病的新一代测序平台应包括对这些区域的覆盖。
