Mutation screening of the RYR1-cDNA from peripheral B-lymphocytes in 15 Swedish malignant hyperthermia index cases.
BACKGROUND
Malignant hyperthermia (MH), linked to the ryanodine receptor 1 gene (RYR1) on chromosome 19, is a potentially lethal pharmacogenetic disorder which may lead to a disturbance of intracellular calcium homeostasis when susceptible individuals are exposed to halogenated anaesthetics, suxamethonium, or both. Central core disease (CCD) is a rare dominantly inherited congenital myopathy allelic to MH-susceptibility.


METHODS
In this study, 14 unrelated MH-susceptible probands and one CCD patient from Sweden were screened for mutations in the RYR1. Since the RYR1 is also expressed in B-lymphocytes, RYR1-cDNA was transcribed from total RNA extracted from white blood cells.


RESULTS
We detected two known RYR1 mutations and two previously described unclassified sequence variants. In addition, six novel sequence variants were detected. All mutations or sequence variants were verified on genomic DNA. Seven of the probands did not show any candidate mutation, although the total coding region of RYR1 was sequenced. Segregation data in in vitro contracture tested family members of three probands support a causative role of three of the novel sequence variants.


CONCLUSIONS
Our study contributes to the genetic aetiology of MH in Sweden, but also raises questions about the involvement of genes other than RYR1 since nearly half of the probands did not show any sequence variants in the total coding region of the RYR1.
Broman
M
M
Department of Anaesthesiology and Intensive Care, Lund University Hospital, S-22185 Lund, Sweden. marcus.broman@skane.se
Gehrig
A
A
Islander
G
G
Bodelsson
M
M
Ranklev-Twetman
E
E
Rüffert
H
H
Müller
C R
CR
D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000737:chemistry*; D002648:Child; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D017124:Conserved Sequence; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008305:Malignant Hyperthermia / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*
D018076:DNA, Complementary; D019837:Ryanodine Receptor Calcium Release Channel