Clinical and Genetic Findings in a Large Cohort of Patients with Ryanodine Receptor 1 Gene-Associated Myopathies
Clinical and Genetic Findings in a Large Cohort of Patients with Ryanodine Receptor 1 Gene-Associated Myopathies
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DOI：
10.1002/humu.22056
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发表时间：
2012-06-01
期刊：
影响因子：
3.9
通讯作者：
Muntoni, Francesco
中科院分区：
文献类型：
--
作者：
Klein, Andrea;Lillis, Suzanne;Muntoni, Francesco
Ryanodine受体1 （RYR1）突变是先天性肌病的常见原因，与显性和隐性遗传相关。组织病理学表现通常为中心核或多微核，更罕见的是1型优势/均匀性，纤维型不平衡，内部成核增加，脂肪和结缔组织。我们描述了71个家族，其中35个与显性RYR1突变有关，36个与隐性遗传有关。5个显性突变和55个隐性突变中的35个以前没有报道过。显性突变多位于已识别的突变热点区域，而隐性突变分布在整个编码序列中。隐性突变包括无义突变和剪接突变，预计会导致RyR1蛋白的减少。临床差异很大。作为一个群体，显性突变与较温和的表型相关；隐性遗传患者起病早、虚弱多、功能受限。眼外肌和球外肌受累在隐性组中几乎完全可见。总之，我们的研究报告了大量新的RYR1突变，并表明隐性变异至少与显性变异一样频繁。确定新突变的致病性通常是困难的，在临床、组织学和肌肉磁共振成像结果的背景下解释遗传结果是必不可少的。[j] .中国生物医学工程学报，2012。(C) 2012 Wiley期刊公司
Ryanodine receptor 1 (RYR1) mutations are a common cause of congenital myopathies associated with both dominant and recessive inheritance. Histopathological findings frequently feature central cores or multiminicores, more rarely, type 1 predominance/uniformity, fiber-type disproportion, increased internal nucleation, and fatty and connective tissue. We describe 71 families, 35 associated with dominant RYR1 mutations and 36 with recessive inheritance. Five of the dominant mutations and 35 of the 55 recessive mutations have not been previously reported. Dominant mutations, typically missense, were frequently located in recognized mutational hotspot regions, while recessive mutations were distributed throughout the entire coding sequence. Recessive mutations included nonsense and splice mutations expected to result in reduced RyR1 protein. There was wide clinical variability. As a group, dominant mutations were associated with milder phenotypes; patients with recessive inheritance had earlier onset, more weakness, and functional limitations. Extraocular and bulbar muscle involvement was almost exclusively observed in the recessive group. In conclusion, our study reports a large number of novel RYR1 mutations and indicates that recessive variants are at least as frequent as the dominant ones. Assigning pathogenicity to novel mutations is often difficult, and interpretation of genetic results in the context of clinical, histological, and muscle magnetic resonance imaging findings is essential. Hum Mutat 33: 981-988, 2012. (C) 2012 Wiley Periodicals, Inc.