Evidence for Genetic Heterogeneity of Malignant Hyperthermia Susceptibility

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 1992 Jun 1

PMID 1598899

Citations 13

Authors

T Deufel

A Golla

D Iles

A Meindl

T Meitinger

D Schindelhauer

A DeVries

D Pongratz

D H Maclennan

K J Johnson

Affiliations

Soon will be listed here.

Abstract

A locus for malignant hyperthermia susceptibility (MHS) has been localized on chromosome 19q12-13.2, while at the same time the gene encoding the skeletal muscle ryanodine receptor (RYR1) also has been mapped to this region and has been found to be tightly linked to MHS. RYR1 was consequently postulated as the candidate for the molecular defect causing MHS, and a point mutation in the gene has now been identified and is thought to be the cause of MH in at least some MHS patients. Here we report the results of a linkage study done with 19q12-13.2 markers, including the RYR1 cDNA, in two Bavarian families with MHS. In one of the families, three unambiguous recombination events between MHS and the RYR1 locus were found. In the second family only one informative meiosis was seen with RYR1. However, segregation analysis with markers for D19S75, D19S28, D19S47, CYP2A, BCL3, and APOC2 shows that the crossovers in the first family involve the entire haplotype defined by these markers flanking RYR1 and, furthermore, reveals multiple crossovers between these haplotypes and MHS in the second family. In these families, pairwise and multipoint lod scores below -2 exclude MHS from an interval spanning more than 26 cM and comprising the RYR1 and the previously described MHS locus. Our findings thus strongly suggest genetic heterogeneity of the MHS trait and prompt the search for another MHS locus.

Citing Articles

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Voltage-dependent calcium release in human malignant hyperthermia muscle fibers.

Struk A, Lehmann-Horn F, Melzer W Biophys J. 1998; 75(5):2402-10.

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Genetic heterogeneity and HOMOG analysis in British malignant hyperthermia families.

Robinson R, Curran J, Hall W, Halsall P, Hopkins P, Markham A J Med Genet. 1998; 35(3):196-201.

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Intracellular calcium homeostasis in human primary muscle cells from malignant hyperthermia-susceptible and normal individuals. Effect Of overexpression of recombinant wild-type and Arg163Cys mutated ryanodine receptors.

Censier K, Urwyler A, Zorzato F, Treves S J Clin Invest. 1998; 101(6):1233-42.

PMID: 9502764 PMC: 508677. DOI: 10.1172/JCI993.

Genetic heterogeneity in Schwartz-Jampel syndrome: two families with neonatal Schwartz-Jampel syndrome do not map to human chromosome 1p34-p36.1.

Brown K, Al-Gazali L, Moynihan L, Lench N, Markham A, MUELLER R J Med Genet. 1997; 34(8):685-7.

PMID: 9279765 PMC: 1051035. DOI: 10.1136/jmg.34.8.685.

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