Identification of a Novel Ryanodine Receptor Mutation Causing Malignant Hyperthermia

Malignant hyperthermia (MH) is a potentially fatal autosomal dominant disorder of the skeletal muscle and is triggered in susceptible individuals by commonly used inhalation anaesthetics and depolarizing muscle relaxants. Around 80% of the affected family are linked to the ryanodine receptor (RYR1) gene. More than 300 mutations in RYR1 have been associated with the MH-susceptible phenotype. Here we report the identification by two independent methods of a novel mutation associated with the MH-susceptible phenotype in the RYR1 gene. 1. Introduction Malignant hyperthermia susceptibility (MHS; OMIM *145600) is an autosomal, dominantly inherited, potentially fatal pharmacogenetic disturbance of intracellular calcium homeostasis, associated with the ryanodine receptor 1 (RYR1; OMIM *180901) in the sarcoplasmic reticulum of the skeletal muscle cells. In susceptible individuals, volatile or inhalational anaesthetics such as halothane and depolarizing muscle relaxants like succinylcholine can induce severe decompensation of muscle calcium homeostasis [1]. Clinical symptoms of an MH attack are hyperthermia, accelerated muscle metabolism, muscle contractions, metabolic acidosis, and tachycardia, and unless immediately recognised, and treated it is fatal [1]. Because MH is a subclinical myopathy, MHS individuals are asymptomatic during daily life. Outside anaesthesia, the diagnosis of MHS can only be established with specific testing by an in vitro contracture test (IVCT), based on the differential contractile response of normal (MHN) and MHS muscles to halothane and caffeine [2]. IVCT is expensive and invasive as it requires an open muscle biopsy from the quadriceps femoris. Genetic screening of the ryanodine receptor isoform 1 (RYR1) is an alternative method for identifying probands and their family members as MH-susceptible after clinical evidence of MH susceptibility [3]. Molecular genetic testing indicates that mutations in RYR1 are identified in up to 70%–80% of the individuals with confirmed MHS [4]. The majority of mutations appear to be clustered in three hotspots: between exons 2 and 17 encoding amino acid residues from 35 to 614 (MH region 1), between exons 39 and 46 encoding amino acid residues from 2163 to 2458 (MH region 2), and a third region in the 3′ end of the gene is between exons 90 and 106 encoding amino acid residues from 4668 to 4904 (MH region 3) [5]. Here, we report a novel mutation located in the central portion of the RYR1 gene in a Czech family. 2. Materials and Methods We investigated a multigenerational Czech family with two known