Brain Advance Access originally published online on April 18, 2006
Brain 2006 129(6):1470-1480; doi:10.1093/brain/awl077
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Central core disease is due to RYR1 mutations in more than 90% of patients
1 Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP) Kodaira, Tokyo 2 Department of Anesthesiology, Tokyo Rinkai Hospital Tokyo 3 Department of Anesthesiology, Saitama Medical School Saitama, Japan
Correspondence to: Ichizo Nishino, MD, PhD, Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187-8502, Japan E-mail: nishino{at}ncnp.go.jp
Ryanodine receptor 1 (RYR1) gene mutations are associated with central core disease (CCD), multiminicore disease (MmD) and malignant hyperthermia (MH), and have been reported to be responsible for 47–67% of patients with CCD and rare cases with MmD. However, to date, the true frequency and distribution of the mutations along the RYR1 gene have not been determined yet, since mutation screening has been limited to three ‘hot spots’, with particular attention to the C-terminal region. In this study, 27 unrelated Japanese CCD patients were included. Clinical histories and muscle biopsies were carefully reviewed. We sequenced all the 106 exons encoding RYR1 with their flanking exon–intron boundaries, and identified 20 novel and 3 previously reported heterozygous missense mutations in 25 of the 27 CCD patients (93%), which is a much higher mutation detection rate than that perceived previously. Among them, six were located outside the known ‘hot spots’. Sixteen of 27 (59%) CCD patients had mutations in the C-terminal ‘hot spot’. Three CCD patients had a probable autosomal recessive disease with two heterozygous mutations. Patients with C-terminal mutations had earlier onset and rather consistent muscle pathology characterized by the presence of distinct cores in almost all type 1 fibres, interstitial fibrosis and type 2 fibre deficiency. In contrast, patients with mutations outside the C-terminal region had milder clinical phenotype and harbour more atypical cores in their muscle fibres. We also sequenced two genes encoding RYR1-associated proteins as candidate causative genes for CCD: the 12 kD FK506-binding protein (FKBP12) and the 
1 subunit of L-type voltage-dependent calcium channel or dihydropyridine receptor (CACNA1S). However, no mutation was found, suggesting that these genes may not, or only rarely, be responsible for CCD. Our results indicate that CCD may be caused by RYR1 mutations in the majority of patients.
Key Words: central core disease; genotype–phenotype correlation; muscular dystrophy; myopathy; ryanodine receptor 1 mutations
Abbreviations:
CACNA1S, 1 subunit of L-type voltage-dependent calcium channel; CCD, central core disease; CICR, calcium-induced calcium release; EC, excitation–contraction; FKBP12, FK506-binding protein, 12 kD; mGT, modified Gomori–Trichrome; MmD, multiminicore disease; MH, malignant hyperthermia; RYR1, ryanodine receptor 1; SERCA, sarco-endoplasmic reticulum Ca2+ ATPase; SR, sarcoplasmic reticulum
Received October 28, 2005. Revised March 1, 2006. Accepted March 8, 2006.
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