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Human Molecular Genetics, 2003, Vol. 12, No. 10 1171-1178
DOI: 10.1093/hmg/ddg121
© 2003 Oxford University Press

A homozygous splicing mutation causing a depletion of skeletal muscle RYR1 is associated with multi-minicore disease congenital myopathy with ophthalmoplegia

Nicole Monnier1, Ana Ferreiro2, Isabelle Marty3, Annick Labarre-Vila4, Paulette Mezin5 and Joel Lunardi1,6,*

1Laboratoire de Biochimie de l'ADN-EA 2943, CHU Grenoble, France, 2INSERM U 582, Institut de Myologie, Paris, France, 3INSERM EMI 9931 and CIS-DRDC, CEA Grenoble, France, 4Laboratoire EFSN, CHU Grenoble, France, 5Laboratoire de Pathologie Cellulaire, CHU Grenoble, France and 6BECP-EA 2943/DRDC; CEA Grenoble, France

Received January 22, 2003; Accepted March 7, 2003

The ryanodine receptor (RYR1) is an essential component of the calcium homeostasis of the skeletal muscle in mammals. Inactivation of the RYR1 gene in mice is lethal at birth. In humans only missense and in-frame mutations in the RYR1 gene have been associated so far with various muscle disorders including malignant hyperthermia, central core disease and the moderate form of multi-minicore disease (MmD). We identified a cryptic splicing mutation in the RYR1 gene that resulted in a 90% decrease of the normal RYR1 transcript in skeletal muscle. The 14646+2.99 kb A->G mutation was associated with the classical form of MmD with ophthalmoplegia, whose genetic basis was previously unknown. The mutation present at a homozygous level was responsible for a massive depletion of the RYR1 protein in skeletal muscle. The mutation was not expressed in lymphoblastoid cells, pointing toward a tissue specific splicing mechanism. This first report of an out-of-frame mutation that affects the amount of RYR1 raised the question of the amount of RYR1 needed for skeletal muscle function in humans.

* To whom correspondence should be addressed at: Laboratoire Biochimie de l'ADN-EA 2943, CHU Grenoble 217X, 38043 Grenoble Cedex, France. Tel: +33 476765573; Fax: +33 476765837; Email: jlunardi{at}chu-grenoble.fr


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