Identification of the Arg1086His mutation in the alpha subunit of the voltage‐dependent calcium channel (CACNA1S) in a North American family with malignant hyperthermia

Abstract

Individuals from a large North American population were screened for the presence of the mutation in the alpha1 subunit of the voltage-dependent calcium channel (CACNA1S) that has recently been associated with malignant hyperthermia (MH). This Arg1086His mutation was screened for in 154 MH normal (MHN) individuals and 112 MH susceptible (MHS) individuals, who were diagnosed by the North American protocol of the in vitro contracture test. PCR and restriction enzyme analysis was used to test for the mutation. The Arg1086His mutation in the CACNA1S was not found in any of the MHN individuals. In contrast, two related individuals (grandfather and grandson, father and son of the MH proband) among the MHS group exhibited this mutation. However, a third MHS individual in the same family (granddaughter, cousin of the grandson) did not exhibit this mutation. These results indicate that this mutation may be associated with MH in this family. Genetic alterations in the CACNA1S associated with MH are present in approximately 1% of this North American MHS population.

A report of fulminant malignant hyperthermia in a patient with a novel mutation of the CACNA1S gene

“…However, to date only a single CACNA1S mutation, p.Arg1086His, has been identified in association with MH in three independent families. [6][7][8] Although sequencing of the entire RYR1 transcript in our patient did not reveal any mutations, we detected a novel p.Arg1086Ser mutation in our patient's alpha 1 subunit of voltage-sensitive L-type calcium channel gene. This mutation affects the same Arg1086 residue, which substitution for histidine, is associated with MH.…”

“…5 The other MH gene with an identified MH-associated mutation is the CACNA1S gene encoding the a1-subunit of the skeletal muscle L-type calcium channel. [6][7][8] Here we describe the identification of a novel CACNA1S mutation in a patient with a clinical episode of MH.…”

Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population

“…13 For the second causal gene, CACNA1S, only three MH-associated mutations have been reported. [14][15][16][17][18] Genetic testing based on advances in MH genetic research is playing an increasingly important role in MH diagnostics. It has proven to be especially useful in early diagnosis of children and patients who cannot undergo the caffeine-halothane contracture test (CHCT) for MH susceptibility because CHCT requires an invasive muscle biopsy.…”

Frequency and localization of mutations in the 106 exons of theRYR1 gene in 50 individuals with malignant hyperthermia

“…This analysis confirmed the absence of mutations in the RYR1 gene in these 7 subjects, but also indicated that DHPLC analysis represents a highly efficient methodology for RYR1 mutation detection. Mutations in exon 25 of the CACNA1S gene (p.Arg1086His and p.Arg1086Cys) have been reported in two MH probands Stewart et al, 2001]. Thus, exon 25 of the CACNA1S gene of individuals 2, 8, 12, 16, 23, 28 and 29 was analyzed by direct nucleotide sequencing.…”

“…Rare cases of mutations in the α1 subunit of the DHPR gene (CACNA1S: MIM# 114208) have been reported in MH patients Stewart et al, 2001]. Additional loci have also been linked to MH, but causative genes have still to be identified [Levitt et al, 1992;Iles et al, 1994;Sudbrak et al, 1995;Robinson et al, 1998].…”