Luo Sushan, Cai Shuang, Maxwell Susan, Yue Dongyue, Zhu Wenhua, Qiao Kai, Zhu Zhen, Zhou Lei, Xi Jianying, Lu Jiahong, Beeson David, Zhao Chongbo
Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
Neurosciences Group, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
Neuromuscul Disord. 2017 Jun;27(6):557-564. doi: 10.1016/j.nmd.2017.03.004. Epub 2017 Mar 10.
Mutations in the GMPPB gene may underlie both limb girdle muscular dystrophy (LGMD) and congenital myasthenic syndrome (CMS). Forty-one cases have been reported to date and hotspot mutations are emerging in the Caucasian population. Clinical and pathological features of 5 patients with compound heterozygous GMPPB mutations were collected and retrospectively reviewed. In vitro functional analysis was performed to investigate the pathogeneity of GMPPB variants. The patients presented with proximal limb weakness in their first to second decades. Fluctuating muscle weakness, myalgia and calf hypertrophy were the major complaints. Myogenic changes on electromyography and marked attenuation on 3 Hz repetitive nerve stimulation were observed in all patients. Four reported a beneficial response to pyridostigmine. Muscle MRI showed selective involvement in the calf in case 1. Immunolabeling of α-dystroglycan was abnormal for case 1 and case 2. Four novel missense mutations in the C-terminal region of GMPPB were identified, with p.(Arg357His) being present in all the cases. In vitro functional assays demonstrated that these variants did not markedly reduce the amount of GMPPB, but gave rise to an increased propensity for protein aggregation. Increasingly, patients with GMPPB mutations are found to present with an overlapping LGMD/myasthenic syndrome. The mutation spectrum in Chinese patients may differ from that of European populations, with the mutation p.(Arg357His) most frequently found. These mutations may lead to abnormal folding of GMPPB leading to protein aggregates in the cytoplasm rather than an overall loss in protein expression.
GMPPB基因的突变可能是肢带型肌营养不良（LGMD）和先天性肌无力综合征（CMS）的潜在病因。迄今为止已报道了41例病例，并且在白种人群中出现了热点突变。收集并回顾性分析了5例携带复合杂合子GMPPB突变患者的临床和病理特征。进行了体外功能分析以研究GMPPB变异体的致病性。这些患者在10至20岁时出现近端肢体无力。主要症状为波动性肌无力、肌痛和小腿肥大。所有患者均观察到肌电图上的肌源性改变以及3Hz重复神经刺激时的明显衰减。4例患者报告对吡啶斯的明有良好反应。病例1的肌肉MRI显示小腿选择性受累。病例1和病例2的α- dystroglycan免疫标记异常。在GMPPB的C末端区域鉴定出4个新的错义突变，所有病例中均存在p.(Arg357His)。体外功能分析表明，这些变异体并未显著减少GMPPB的量，但导致蛋白质聚集的倾向增加。越来越多的携带GMPPB突变的患者被发现同时患有重叠性LGMD/肌无力综合征。中国患者的突变谱可能与欧洲人群不同，最常见的突变是p.(Arg357His)。这些突变可能导致GMPPB异常折叠，从而在细胞质中形成蛋白质聚集体，而不是蛋白质表达的整体丧失。
