Abstract
BackgroundMalignant hyperthermia (MH) is a dominantly inherited skeletal muscle disorder that can cause a fatal hypermetabolic reaction to general anaesthetics. The primary locus of MH (MHS1 locus) in humans is linked to chromosome 19q13.1, the position of the gene encoding the ryanodine receptor skeletal muscle calcium release channel (RyR1).MethodsIn this study, an inexpensive allele-specific PCR (AS-PCR) assay was designed that allowed the relative quantification of the two RyR1 transcripts in heterozygous samples found to be susceptible to MH (MHS). Allele-specific differences in RyR1 expression levels can provide insight into the observed variable penetrance and variations in MH phenotypes between individuals. The presence/absence of the H4833Y mutation in RYR1 transcripts was employed as a marker that allowed discrimination between the two alleles.ResultsIn four skeletal muscle samples and two lymphoblastoid cell lines (LCLs) from different MHS patients, the wild type allele was found to be expressed at higher levels than the mutant RyR1 allele. For both LCLs, the ratios between the wild type and mutant RYR1 alleles did not change after different incubation times with actinomycin D. This suggests that there are no allele-specific differences in RyR1 mRNA stability, at least in these cells.ConclusionThe data presented here revealed for the first time allele-specific differences in RYR1 mRNA expression levels in heterozygous MHS samples, and can at least in part contribute to the observed variable penetrance and variations in MH clinical phenotypes.
Highlights
Malignant hyperthermia (MH) is a dominantly inherited skeletal muscle disorder that can cause a fatal hypermetabolic reaction to general anaesthetics
The primary locus of MH (MHS1 locus) in humans is linked to chromosome 19q13.1, the position of the gene encoding the ryanodine receptor skeletal muscle calcium release channel (RyR1) [7,8]
Four frozen MHS skeletal muscle tissues stored subsequent to biopsy for in vitro contracture test (IVCT) analysis and two Epstein-Barr virus (EBV)-immortalized lymphoblastoid cell lines (LCLs) derived from blood of MHS individuals carrying the causative H4833Y MH mutation, were used after informed consent from participating subjects
Summary
Malignant hyperthermia (MH) is a dominantly inherited skeletal muscle disorder that can cause a fatal hypermetabolic reaction to general anaesthetics. 145600], first described by Denborough and Lovell [1], is a dominantly inherited skeletal muscle disorder that predisposes susceptible individuals to a potentially fatal reaction during general anaesthesia [2]. Besides this toxic response to anaesthetics, in rare circumstances MH may be triggered in susceptible individuals by severe exercise in hot conditions, infections, neuroleptic drugs, or overheating in infants [3]. 180901, GenBank: NM_000540] is linked to congenital myopathies namely, central core disease (CCD) [MIM no. Besides MH, the RYR1 gene [MIM no. 180901, GenBank: NM_000540] is linked to congenital myopathies namely, central core disease (CCD) [MIM no. 117000] and multi minicore disease (MmD) [MIM no. 255320]
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