Mutations in GMPPB cause congenital myasthenic syndrome and bridge myasthenic disorders with dystroglycanopathies.
Mutations in GMPPB cause congenital myasthenic syndrome and bridge myasthenic disorders with dystroglycanopathies.
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DOI：
10.1093/brain/awv185
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发表时间：
2015-09
期刊：
影响因子：
--
通讯作者：
Beeson D
中科院分区：
文献类型：
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作者：
Belaya K;Rodríguez Cruz PM;Liu WW;Maxwell S;McGowan S;Farrugia ME;Petty R;Walls TJ;Sedghi M;Basiri K;Yue WW;Sarkozy A;Bertoli M;Pitt M;Kennett R;Schaefer A;Bushby K;Parton M;Lochmüller H;Palace J;Muntoni F;Beeson D
先天性肌无力综合征与神经肌肉传递障碍有关。Belaya等人表明，糖基化途径酶GMPPB的突变也会引起先天性肌无力综合征，该酶先前与肌营养不良性肌营养不良症有关。这种鉴别诊断是重要的，以确保受影响的个人得到适当的药物治疗。先天性肌无力综合征与神经肌肉传递障碍有关。Belaya等人表明，糖基化途径酶GMPPB的突变也会引起先天性肌无力综合征，该酶先前与肌营养不良性肌营养不良症有关。这种鉴别诊断是重要的，以确保受影响的个人得到适当的药物治疗。先天性肌无力综合征是由神经肌肉接头处的信号传递受损引起的遗传性疾病。已知至少有20个基因的突变会导致这些疾病的发生。其中四种，ALG2，ALG14，DPAGT 1和GFPT1，参与糖基化。在这里，我们确定了第五个糖基化基因，GMPPB，突变导致先天性肌无力综合征。首先，我们确定了隐性突变，从五个亲属定义为先天性肌无力综合征使用递减的复合肌肉动作电位重复神经刺激肌电图的7例。通过GMPPB的长度存在突变，并且使用分离、计算机分析、外显子捕获、细胞转染、随后的蛋白质印迹和免疫染色来确定致病性。GMPPB先天性肌无力综合征病例显示出先天性肌无力综合征亚型的临床特征，这些亚型是由于糖基化缺陷引起的，具有近端肢体肌肉群的可变无力，而面部和眼部肌肉在很大程度上幸免。然而，患有GMPPB先天性肌无力综合征的患者具有更突出的肌病特征，可以通过肌肉活检、肌电图、肌肉磁共振成像和血清肌酸激酶水平升高来检测。最近有报道称GMPPB的突变会导致肌营养不良症的发生。通过肌电图分析另外4例GMPPB相关的肌营养不良性肌营养不良症病例发现，神经肌肉接头部分并不总是存在缺陷。因此，我们发现GMPPB的突变可以导致广泛的临床特征，其中神经肌肉传递缺陷是病例子集的主要组成部分。临床识别GMPPB相关的先天性肌无力综合征可能会因肌病特征的存在而变得复杂，但正确的诊断是重要的，因为受影响的个体可以对适当的治疗作出反应。
Congenital myasthenic syndromes are associated with impairments in neuromuscular transmission. Belaya et al. show that mutations of the glycosylation pathway enzyme GMPPB, which has previously been implicated in muscular dystrophy dystroglycanopathy, also cause a congenital myasthenic syndrome. This differential diagnosis is important to ensure that affected individuals receive appropriate medication. Congenital myasthenic syndromes are associated with impairments in neuromuscular transmission. Belaya et al. show that mutations of the glycosylation pathway enzyme GMPPB, which has previously been implicated in muscular dystrophy dystroglycanopathy, also cause a congenital myasthenic syndrome. This differential diagnosis is important to ensure that affected individuals receive appropriate medication. Congenital myasthenic syndromes are inherited disorders that arise from impaired signal transmission at the neuromuscular junction. Mutations in at least 20 genes are known to lead to the onset of these conditions. Four of these, ALG2, ALG14, DPAGT1 and GFPT1, are involved in glycosylation. Here we identify a fifth glycosylation gene, GMPPB, where mutations cause congenital myasthenic syndrome. First, we identified recessive mutations in seven cases from five kinships defined as congenital myasthenic syndrome using decrement of compound muscle action potentials on repetitive nerve stimulation on electromyography. The mutations were present through the length of the GMPPB, and segregation, in silico analysis, exon trapping, cell transfection followed by western blots and immunostaining were used to determine pathogenicity. GMPPB congenital myasthenic syndrome cases show clinical features characteristic of congenital myasthenic syndrome subtypes that are due to defective glycosylation, with variable weakness of proximal limb muscle groups while facial and eye muscles are largely spared. However, patients with GMPPB congenital myasthenic syndrome had more prominent myopathic features that were detectable on muscle biopsies, electromyography, muscle magnetic resonance imaging, and through elevated serum creatine kinase levels. Mutations in GMPPB have recently been reported to lead to the onset of muscular dystrophy dystroglycanopathy. Analysis of four additional GMPPB-associated muscular dystrophy dystroglycanopathy cases by electromyography found that a defective neuromuscular junction component is not always present. Thus, we find mutations in GMPPB can lead to a wide spectrum of clinical features where deficit in neuromuscular transmission is the major component in a subset of cases. Clinical recognition of GMPPB-associated congenital myasthenic syndrome may be complicated by the presence of myopathic features, but correct diagnosis is important because affected individuals can respond to appropriate treatments.