Prior to the start of this programme malignant hyperthermia was believed to be a single gene disorder due to one mutation. The Arg614Cys mutation in the skeletal muscle ryanodine receptor gene (RYR1) was thought to be responsible for the MH phenotype in humans. To date, over 23 missense mutations associated with MH have been described in the RYR1 gene.
A diagnostic service where individuals are screened for the presence of reported MH mutations is currently offered in South Africa. Subsequent to haplotype and linkage analysis of the South African MH population it was realised that not all the South African MH families displayed linkage to the RYR1 locus on chromosome 19q.
At the time (1992) we postulated that the MH phenotype could result from mutations in several genes involved in skeletal muscle contraction – thus that genetic heterogeneity exists in MH.
Confirmation of genetic heterogeneity was generated via a candidate gene approach when linkage between a second MH locus, on chromosome 17q, was identified. These linkage results have subsequently been confirmed by an independent study.
Currently, the hypothesis of genetic heterogeneity in MH is accepted due to the fact that six loci, on chromosomes 19q, 17q, 7q, 3q, 5p and 1q, have been associated with the MH phenotype. The seventh MH locus was identified via linkage screening of the human genome. This locus, recently described by us, is located on chromosome 2q.
Unique contributions (first reports) from this research programme to current understanding of the genetic basis of MH can be summarised below:
- Genetic heterogeneity exists in malignant hyperthermia.
- Linkage of the MH phenotype to a novel locus on chromosome 17q.
- Genotype-phenotype discordance exists with regard to the Arg614Cys mutation in the RYR1 gene.
- A novel glycine1306-to-alanine mutation associated with masseter muscle rigidity (MMR) in the adult muscle sodium channel a-subunit gene.
- The only two MH mutations thus far detected in the South African MH population were described.
- A novel MH locus on chromosome 2q was described in the human genome.
Characterisation of the locus on chromosome 2q is currently the focus of this research programme. Future objectives include mutation analysis at this locus as well as phenotype-genotype correlation in MH. Collaborators on this multi-disciplinary research programme are listed below.
Current and previous collaborators were from the following institutions:
- Centre for Genome Research, North-West University.
- Department of Anaesthesiology, University of Pretoria, South Africa.
- Dept. of Anesthesiology and Critical Care Medicine, Thomas Jefferson University, Philadelphia, PA, U.S.A.
- Dept. of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, U.S.A.).
- Dept. of Anesthesiology, Allegheney University of the Health Sciences, PA, U.S.A.
- Centre for the Genetics of Asthma and Complex Diseases, University of Maryland, Baltimore, MD, U.S.A.
- Dept. of Physiology, Johns Hopkins Medical Institutions, Baltimore, MD, U.S.A.
- Dept. of Human Genetics, Marshfield Medical Research Centre, Marshfield, WI, U.S.A.