MALIGNANT HYPERTHERMIA SUSCEPTIBILITY--MOLECULAR STUDIES

恶性高热易感性（MHS）是一种潜在的致命疾病， 骨骼肌代谢常染色体显性遗传病。 虽然MHS 是罕见的，它仍然是由于麻醉死亡的一个重要原因。 最近，McCarthy等人报告了 MHS至染色体19 ql 2 - 13.2。此外，MacLennan等人建议， 连锁数据的基础是兰尼碱受体基因的缺陷 （RYDR）导致这种疾病。 然而，遗传异质性一直很好， 在MHS中描述。 我们在这里报告扩展单倍型分析与标记 在19 ql 3。113.2确认分子异质性的连锁群 在这种混乱中。 我们的数据表明，RYDR中的缺陷不可能是 导致两个不相关家族出现MHS症状的人 的 本提案的目标（将同时审议） 评估MHS的遗传异质性， 敏感脂肪酶（LIPE）作为候选基因。 LIPE是 被认为是基因候选者，因为它的两侧是相同的基因， 在19 q上标记为MHS。 LIPE还调节游离脂肪酸（FFA） 代谢，FFA在MHS肌肉中异常升高，这可以解释 在这种疾病中观察到的许多病理生理学发现。 因此，为了实现我们的目的，我们建议（1）。以识别 LIPE内的多态性，并将其用于连锁研究，以评估它 作为基因候选人。 如果在LIPE和 MHS表型，我们将评估LIPE cDNA序列的缺陷 导致了这种紊乱（2.）为了评估MHS的异质性，我们将 确定50个家庭，由先证者确定有2个或更多受影响的同胞 北美恶性高热症 集团协议;（3.）创建一个MHS家庭DNA资源提供给所有 研究人员通过从每个个体中开发永生细胞系 研究;（4.）进行MHS表型和一个 在19 q上的一套完整的DNA标记，并评估是否有一个以上的遗传 基因座产生这种疾病以及该基因映射的位置;（5.）评价 MHS表型和其他基因组DNA多态性之间的联系 在那些19 q上的标记不与 这种混乱。

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.