Localization of the gene encoding the α₂/δ-subunits of the L-type voltage-dependent calcium channel to chromosome 7q and analysis of the segregation of flanking markers in malignant hyperthermia susceptible families

Abstract

Malignant hyperthermia susceptibility (MHS) is an autosomal dominant disorder of skeletal muscle which manifests as a potentially fatal hypermetabolic crisis triggered by commonly used anaesthetic agents. The demonstration of genetic heterogeneity in MHS prompted the investigation of the roles played by calcium regulatory proteins other than the ryanodine receptor (RYR1), which is known to be linked to MHS in fewer than half of the European MHS families studied to date. Previously, we have excluded the genes encoding the skeletal muscle L-type voltage-dependent calcium channel alpha 1-, beta 1- and gamma-subunits as candidates for MHS. In this report, we describe the cloning and partial DNA sequence analysis of the gene encoding the alpha 2/delta-subunits, CACNL2A, and its localization on the proximal long arm of chromosome 7q. A new dinucleotide repeat marker close to CACNL2A was identified at the D7S849 locus and tested for linkage in six MHS families. D7S849 and flanking genetic markers were found to co-segregate with the MHS locus through 11 meioses in one, three-generation family. These results suggest that mutations in or near CACNL2A may be involved in some forms of this heterogeneous disorder.

Architecture of Ca2+ Channel Pore-lining Segments Revealed by Covalent Modification of Substituted Cysteines

“…In Vitro cRNA Synthesis and Electrophysiological MeasurementsHuman heart ␣ 1C and ␣ 1C mutants, ␣ 2 /␦ a (53,54), and human ␤ 3 (55)(56)(57)(58) were linearized for cRNA synthesis using the XbaI, XhoI, and NheI restriction enzymes, respectively. Complementary RNA synthesis was accomplished by employing the T7 mMessage mMachine TM (Ambion).…”

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

“…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]. In recent years, more than 60 mutations in RYR1 have been identified in MH/CCD families [Hamilton, 2005].…”

Multigenerational Brazilian family with malignant hyperthermia and a novel mutation in the RYR1 gene

“…Discordance between CHCT and genetic studies has already been reported (26)(27)(28)(29)(30), indicating that some familial mutations are not found in some MHS members of the family. It is also possible that this discordant individual has another mutation in another part of RYR1 not analyzed or in another gene related to MH (4)(5)(6)(7). Some families that display more than one causative mutation leading to MH have been reported (16,31).…”

“…MH susceptibility has been linked to several loci in the genome (4)(5)(6)(7)(8), but most cases are associated with the RYR1 gene located on chromosome 19 (9,10), one of the largest and most complex genes in the human genome, comprising 106 exons and transcribing a 15,117 nucleotide-long RNA (11), which encodes a 563-kD homotetrameric protein. Worldwide, about 70-80% of MH-susceptible (MHS) individuals have mutations in RYR1 (12)(13)(14)(15).…”