Analysis of genetic linkage in malignant hyperthermia susceptible families in Japan

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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.