Human Molecular Genetics, 2001, Vol. 10, No. 22 2581-2592
© 2001 Oxford University Press
Familial and sporadic forms of central core disease are associated with mutations in the C-terminal domain of the skeletal muscle ryanodine receptor
1Laboratoire de Biochimie de l’ADN, CHU Grenoble, Grenoble, France, 2INSERM U523 and Institut de Myologie, Hôpital de la Salpétrière, Paris, France, 3Département de Pédiatrie, CHU Bicêtre, Le Kremlin-Bicêtre, France, 4Département d’Anesthésie, Hôpital Robert Debré, Paris, France and 5Laboratoire BECP/DBMS, EA 2943 UJF—CEA, Grenoble, France
Central core disease (CCD) is an autosomal dominant congenital myopathy. Diagnosis is based on the presence of cores in skeletal muscles. CCD has been linked to the gene encoding the ryanodine receptor (RYR1) and is considered to be an allelic disease of malignant hyperthermia susceptibility. However, the report of a recessive form of transmission together with a variable clinical presentation has raised the question of the genetic heterogeneity of the disease. Analyzing a panel of 34 families exclusively recruited on the basis of both clinically and morphologically expressed CCD, 12 different mutations of the C-terminal domain of RYR1 have been identified in 16 unrelated families. Morphological analysis of the patients’ muscles showed different aspects of cores, all of them associated with mutations in the C-terminal region of RYR1. Furthermore, we characterized the presence of neomutations in the RyR1 gene in four families. This indicates that neomutations into the RyR1 gene are not a rare event and must be taken into account for genetic studies of families that present with congenital myopathies type ‘central core disease’. Three mutations led to the deletion in frame of amino acids. This is the first report of amino acid deletions in RYR1 associated with CCD. According to a four-transmembrane domain model, the mutations concentrated mostly in the myoplasmic and luminal loops linking, respectively, transmembrane domains T1 and T2 or T3 and T4 of RYR1.
+ To whom correspondence should be addressed at: Laboratoire Biochimie de l’ADN, EA 2943 UJF, CHU Grenoble BP 217, 38043 Grenoble Cedex, France. Tel: +33 4 76 76 55 73; Fax: +33 4 76 76 58 37; Email: jlunardi@chu-grenoble.fr
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