MALIGNANT HYPERTHERMIA SUSCEPTIBILITY--MOLECULAR STUDIES

恶性高温易感性(MHS)是一种潜在的致命性 常染色体显性遗传性骨骼肌代谢障碍。尽管MHS 很少见，它仍然是麻醉致死的重要原因。 最近，麦卡锡等人。报告了一个初步的次区域地点 MHS位于染色体19ql2-l3.2。此外，MacLennan等人。建议启用 兰尼定受体基因缺陷的连锁数据基础 (RYDR)导致这种疾病。然而，遗传异质性一直很好。 在MHS中描述。我们在此报告使用标记进行扩展的单倍型分析 在19ql3。确认分子异质性的113.2个连接基 在这种混乱中。我们的数据表明，RYDR的缺陷不可能是 对两个没有血缘关系的家庭的MHS症状负责。这个 当前提案的目标(将同时审查) 是评估MHS的遗传异质性和评估荷尔蒙 敏感脂肪酶(LIPE)作为一种候选基因。利佩是 建议作为候选基因，因为它的侧翼有相同的基因 标记为19q的MHS。LIPE还调节游离脂肪酸(FFA) 代谢和游离脂肪酸在肌肉中异常升高，这可能解释了 在这种疾病中观察到的许多病理生理学发现。 因此，为了达到我们的目的，我们提出(1)。要确定 LIPE内的多态，并将其用于连锁研究以评估它 作为基因候选者。如果在Lipe和Lipe之间没有发现重组子 MHS表型我们将评估LIPE cDNA序列的缺陷 这导致了这种紊乱。(2)为了评估MHS的异构性，我们将 确定50个家庭，由有2个或更多受影响的兄弟姐妹的先证者确定 已经被北美恶性高热症表型鉴定 团体议定书；(3.)创建可供所有人使用的MHS家庭DNA资源 研究人员通过培养每个个体的永生细胞系 研究；(4)进行MHS表型和 19q上的一套完整的DNA标记并评估是否有一个以上的基因 产生这种疾病的基因座和这个基因(S)定位的地方；评估 MHS表型与其他家系DNA多态的关联 19q上的标记不与之共分离的家系中的染色体 这种紊乱。

Malignant hyperthermia susceptibility (MHS) is a potentially lethal autosomal dominant disorder of skeletal muscle metabolism. Although MHS is rare it remains an important cause of death due to anesthesia. Recently, McCarthy et al. reported a preliminary subregional location for MHS to chromosome 19ql2-l3.2. In addition, MacLennan et al. suggested on the basis of linkage data that a defect in the ryanodine receptor gene (RYDR) causes this disorder. However, genetic heterogeneity has been well described in MHS. We report here extended haplotype analyses with markers in the 19ql3. 113.2 linkage groups that confirms molecular heterogeneity in this disorder. Our data demonstrate that a defect in RYDR could not be responsible for the symptoms of MHS in two unrelated families. The objectives of the current proposal (which will be examined simultaneously) are to evaluate genetic heterogeneity in MHS and evaluate the hormone sensitive lipase (LIPE) as an alternative gene candidate. LIPE is suggested as a gene candidate because it is flanked by the same genetic markers as MHS on 19q. LIPE also regulates free fatty acid (FFA) metabolism, and FFA are abnormally elevated in MHS muscle which may explain many of the observed pathophysiologic findings in this disorder. Therefore, in order to achieve our purposes, we propose (1.) to identify polymorphisms within LIPE and use them in linkage studies to evaluate it as a gene candidate. If no recombinants are identified between LIPE and the MHS phenotype we will evaluate the LIPE cDNA sequence for a defect which causes this disorder. (2.) to evaluate heterogeneity in MHS we will ascertain 50 families, identified by a proband with 2 or more affected sibs which have been phenotyped by the North American Malignant Hyperthermia Group Protocol; (3.) to create a MHS FAMILY DNA RESOURCE available to all investigators by developing immortal cell lines from each individual studied; (4.) to conduct linkage analyses between the MHS phenotype and a complete set of DNA markers on 19q and evaluate if more than one genetic locus produces this disorder and where this gene(s) maps; (5.) to evaluate linkage between the MHS phenotype and DNA polymorphisms on other chromosomes in those families where markers on 19q do not cosegregate with this disorder.