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Analysis of genetic linkage in malignant hyperthermia susceptible families in Japan

日本恶性高热易感家族遗传连锁分析

基本信息

批准号：
06671527
负责人：
KAWAMOTO Masashi
金额：
$ 1.09万
依托单位：
HIROSHIMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06671527/
关键词：
Malignant hyperthermia Gene Genetic linkage analysis Skeletal muscle Skinned fiber PCR リアノジン受容体 Ca-induced Ca release

项目摘要

By using linkage-analysis of RYR1 gene polymorphism, we investigated the relation between genetic evidence of RYR1 abnormalities and accelerated rate of Ca-induced Ca release (CICR) mechanism of sarcoplasmic reticulum in skeletal muscle from malignant hyperthermia susceptible (MHS) subjects and families in Japan. Of 72 subjects referred to our institute for further investigation of MHS,26 subjects received skeletal muscle biopsy for the measurement of CICR rate by the skinned fiber method. By sampling venous blood, DNA samples were also obtained from the subjects in these 26 unrelated families. Analyzes of restriction fragment length polymorphism (RFLP) on RYR1 locus and hypervariable microsatellite were performed to investigate the relation between RYR1 abnormalities and acceleration of CICR rate.Accelerated CICR rate was observed in 4 subjects who presented clinically fulminant malignant hyperthemia (MH) and in their 3 relatives. Analysis for substitution of C1840T was performed in 72 subjects, while no alteration was demonstrated. However, we could determine one family as MHS because informative polymorphism suggested the linkage between the acceleration of CICR rate and RYR1 gene. In this family, the linkage study of RYR1 gene would be useful for further investigation of MHS.If the relation is determined between heterogeneity of MH and acceleration of CICR rate, we believe that the genetic test could replace the CICR test as a diagnostic tool for MH.Because occurrence of MH is rare (1 of 74,000 general anesthesias) and a few of MHS subjects may receive the invasive muscle biopsy, we conclude that it is necessary to improve the genetic test and to determine the relation for the investigation of MH in Japan.

通过RYR1基因多态性的连锁分析，研究了日本恶性高热易感（MHS）人群和家庭骨骼肌肌浆网Ca诱导Ca释放加速机制与RYR1基因异常的遗传证据之间的关系。在我院进行MHS进一步调查的72例受试者中，26例接受骨骼肌活检，采用皮纤维法测量CICR率。通过静脉血采样，还获得了这26个不相关家庭的DNA样本。通过对RYR1位点限制性内切片段长度多态性（RFLP）和高变微卫星的分析，探讨了RYR1异常与CICR率加速的关系。4例临床表现为暴发性恶性高热症（MH）的患者及其3例亲属的CICR加速。对72名受试者进行了C1840T的替代分析，未发现任何改变。然而，我们可以确定一个家族为MHS，因为信息多态性表明CICR率加速与RYR1基因之间存在联系。在该家族中，对RYR1基因的连锁研究将有助于进一步研究MHS。如果确定MH异质性与CICR率加速之间的关系，我们认为基因检测可以取代CICR检测作为MH的诊断工具。由于MH的发生率很低（74,000全身麻醉中有1例），并且少数MHS受试者可能接受有创性肌肉活检，我们认为有必要改进基因检测并确定其与MH调查的关系。