Project: Research project


Malignant hyperthermia susceptibility (MHS) is a potentially lethal
autosomal dominant disorder of skeletal muscle metabolism. Although MHS
is rare it remains an important cause of death due to anesthesia.
Recently, McCarthy et al. reported a preliminary subregional location for
MHS to chromosome 19ql2-l3.2. In addition, MacLennan et al. suggested on
the basis of linkage data that a defect in the ryanodine receptor gene
(RYDR) causes this disorder. However, genetic heterogeneity has been well
described in MHS. We report here extended haplotype analyses with markers
in the 19ql3. 113.2 linkage groups that confirms molecular heterogeneity
in this disorder. Our data demonstrate that a defect in RYDR could not be
responsible for the symptoms of MHS in two unrelated families. The
objectives of the current proposal (which will be examined simultaneously)
are to evaluate genetic heterogeneity in MHS and evaluate the hormone
sensitive lipase (LIPE) as an alternative gene candidate. LIPE is
suggested as a gene candidate because it is flanked by the same genetic
markers as MHS on 19q. LIPE also regulates free fatty acid (FFA)
metabolism, and FFA are abnormally elevated in MHS muscle which may explain
many of the observed pathophysiologic findings in this disorder.
Therefore, in order to achieve our purposes, we propose (1.) to identify
polymorphisms within LIPE and use them in linkage studies to evaluate it
as a gene candidate. If no recombinants are identified between LIPE and
the MHS phenotype we will evaluate the LIPE cDNA sequence for a defect
which causes this disorder. (2.) to evaluate heterogeneity in MHS we will
ascertain 50 families, identified by a proband with 2 or more affected sibs
which have been phenotyped by the North American Malignant Hyperthermia
Group Protocol; (3.) to create a MHS FAMILY DNA RESOURCE available to all
investigators by developing immortal cell lines from each individual
studied; (4.) to conduct linkage analyses between the MHS phenotype and a
complete set of DNA markers on 19q and evaluate if more than one genetic
locus produces this disorder and where this gene(s) maps; (5.) to evaluate
linkage between the MHS phenotype and DNA polymorphisms on other
chromosomes in those families where markers on 19q do not cosegregate with
this disorder.
Effective start/end date7/1/916/30/96


  • National Institutes of Health: $282,287.00
  • National Institutes of Health: $258,641.00
  • National Institutes of Health
  • National Institutes of Health


Malignant Hyperthermia
Ryanodine Receptor Calcium Release Channel
Genetic Heterogeneity
Nonesterified Fatty Acids
Genetic Markers
Information Storage and Retrieval
Cause of Death
Skeletal Muscle
Complementary DNA


  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)