title: Identification of heterozygous and homozygous individuals with the novel RYR1 mutation Cys35Arg in a large kindred.
abstract: BACKGROUND
  Malignant hyperthermia (MH) is a potentially fatal, often autosomal dominant, disorder of skeletal muscle and is triggered in susceptible people by all commonly used inhalational anesthetics. In this article, the authors describe a malignant hyperthermia susceptible (MHS) kindred in which both parents of the proband are MHS and are first-degree cousins. Haplotype analysis in this kindred with chromosome 19 linked markers revealed that the proband and another sibling were homozygous for the affected RYR1 allele.
  
  
  METHODS
  Eighteen members of this large pedigree were investigated, with a clinical examination for signs of a myopathy, a caffeine halothane contracture test, a histo-enzymologic study on the muscle biopsies, and linkage analysis on genomic DNA isolated from family blood samples. RYR1 cDNA was amplified by polymerase chain reaction and was cloned and sequenced, facilitating mutation detection.
  
  
  RESULTS
  Linkage analysis demonstrated linkage between RYR1-linked markers and MH susceptibility in this family. DNA sequencing identified a T to C transition at nucleotide position 103, resulting in the substitution of an arginine for cysteine 35, representing the most N-terminal mutation reported to date in the RYR1 gene. This mutation segregates fully with the MHS trait, generating a lod score of 4.65 in favor of linkage to MHS at a recombination frequency of 0.0.
  
  
  CONCLUSIONS
  The proband in this kindred is the first reported homozygote to have presented with an MH episode. The homozygotes in this pedigree do not have an overt myopathy. The sensitivity of muscle samples to caffeine clearly distinguished the two homozygotes from other heterozygous-susceptible individuals. No clear differentiation was observed with the halothane contracture results.
authors.affiliation: Anesthesiology Department, Hôpital Roger Salengro, Lille, France.
authors.forename: P J
authors.initials: PJ
authors.lastname: Lynch
authors.forename: R
authors.initials: R
authors.lastname: Krivosic-Horber
authors.forename: H
authors.initials: H
authors.lastname: Reyford
authors.forename: N
authors.initials: N
authors.lastname: Monnier
authors.forename: K
authors.initials: K
authors.lastname: Quane
authors.forename: P
authors.initials: P
authors.lastname: Adnet
authors.forename: G
authors.initials: G
authors.lastname: Haudecoeur
authors.forename: I
authors.initials: I
authors.lastname: Krivosic
authors.forename: T
authors.initials: T
authors.lastname: McCarthy
authors.forename: J
authors.initials: J
authors.lastname: Lunardi
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000235:genetics; D015220:Calcium Channels / Q000235:genetics*; D002648:Child; D003241:Consanguinity; D003402:Creatine Kinase / Q000097:blood; D003545:Cysteine / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004198:Disease Susceptibility; D005260:Female; D008040:Genetic Linkage; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008305:Malignant Hyperthermia / Q000235:genetics*; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D019837:Ryanodine Receptor Calcium Release Channel; D017386:Sequence Homology, Amino Acid
chemical_list: D015220:Calcium Channels; D018076:DNA, Complementary; D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D001120:Arginine; D003402:Creatine Kinase; D003545:Cysteine