Malignant Hyperthermia in North America: Genetic Screening of the Three Hot Spots in the Type I Ryanodine Receptor Gene
Malignant Hyperthermia in North America: Genetic Screening of the Three Hot Spots in the Type I Ryanodine Receptor Gene
复制标题
北美恶性高热：I型Ryanodine受体基因三个热点的基因筛查
DOI：
10.1097/00000542-200410000-00005
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发表时间：
2004
期刊：
影响因子：
8.8
通讯作者：
S. Muldoon
中科院分区：
文献类型：
--
作者：
Y. Sei;N. Sambuughin;E. Davis;Daniel Sachs;P. Cuenca;B. Brandom;Timothy J. Tautz;H. Rosenberg;T. Nelson;S. Muldoon
背景：恶性高热（MH）是一种骨骼肌药物遗传学疾病，表现为暴露于麻醉剂后危及生命的代谢亢进危机。 I 型兰尼定受体 1 是导致 MH 易感性以及中枢性核心疾病（一种导致 MH 易感性的先天性肌病）的主要基因。 RyR1 基因簇在三个编码区（N 末端、中央和 C 末端区域）有超过 40 个突变。然而，尚未在北美 MH 易感人群中研究每个区域的突变频率。方法：作者测试了 124 名具有 MH 易感性的无关患者的 N 末端（外显子 2、6、9、11、12 和 17）、中央（外显子 39、40、44、45 和 46）和 C 末端（外显子 95、100、101 和 102）区域是否存在突变。结果：124 名 MH 易感患者中的 29 名 (23%) 中发现了 14 种突变。大约 70% 的突变（包括新突变 Ala 2437Val）位于中心区域。在 8 名患者 (28%) 中，在 N 末端区域发现了突变。在一名诊断为中央核心疾病的患者中，筛查 C 末端区域发现了一种新的突变 Leu4824Pro。结论：通过2002年北美共识小组中列出的突变（或外显子）筛查，突变检出率仅为23%。这项研究的结果表明，首先测试中部地区是目前对北美人群最有效的筛查策略。可能需要在三个热点中筛选更多外显子才能找到 RyR1 基因突变的准确频率。
Background:Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle, manifested as a life-threatening hypermetabolic crisis after exposure to anesthetics. Type I ryanodine receptor 1 is the primary gene responsible for susceptibility to MH as well as central core disease, a congenital myopathy that predisposes susceptibility to MH. More than 40 mutations in the RyR1 gene cluster in three coding regions: the N-terminus, central, and C-terminus regions. However, the frequency of mutations in each region has not been studied in the North American MH-susceptible population. Methods:The authors tested 124 unrelated patients with MH susceptibility for the presence of mutations in the N-terminus (exons 2, 6, 9, 11, 12, and 17), central (exons 39, 40, 44, 45, and 46), and C-terminus (exons 95, 100, 101, and 102) regions. Results:Fourteen mutations have been identified in 29 of 124 MH-susceptible patients (23%). Approximately 70% of the mutations, which include a novel mutation, Ala 2437Val, were in the central region. In 8 patients (28%), mutations were identified in the N-terminus region. Screening the C-terminus region yielded a novel mutation, Leu4824Pro, in a single patient with a diagnosis of central core disease. Conclusions:The detection rate for mutations is only 23% by screening mutations (or exons) listed in the 2002 North American consensus panel. The implications from this study suggest that testing the central region first is currently the most effective screening strategy for the North American population. Screening more exons in the three hot spots may be needed to find an accurate frequency of mutations in the RyR1 gene.