Localization of the gene encoding the alpha 2/delta-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

• Published in: Human molecular genetics Vol. 3; no. 6; p. 969
• Main Authors: Iles, D E, Lehmann-Horn, F, Scherer, S W, Tsui, L C, Olde Weghuis, D, Suijkerbuijk, R F, Heytens, L, Mikala, G, Schwartz, A, Ellis, F R
• Format: Journal Article
• Language: English
• Published: England 01-06-1994
• Subjects: Animals; Base Sequence; Blotting, Southern; Calcium Channels - genetics; Chromosome Mapping; Chromosomes, Artificial, Yeast; Chromosomes, Human, Pair 7; Cloning, Molecular; DNA Primers; DNA, Satellite - genetics; Europe; Female; Genetic Linkage; Genetic Markers; Genetic Predisposition to Disease; Humans; Hybrid Cells; In Situ Hybridization, Fluorescence; Macromolecular Substances; Male; Malignant Hyperthermia - genetics; Mice; Molecular Sequence Data; Muscle Proteins - genetics; Muscles - metabolism; Pedigree; Polymorphism, Genetic; Repetitive Sequences, Nucleic Acid; Ryanodine Receptor Calcium Release Channel; Europe
• ISSN: 0964-6906
• DOI: 10.1093/hmg/3.6.969

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.