Skip Navigation



Brain Advance Access published online on April 18, 2006
Brain, doi:10.1093/brain/awl077
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
129/6/1470    most recent
awl077v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Wu, S.
Right arrow Articles by Nishino, I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wu, S.
Right arrow Articles by Nishino, I.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author (2006). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received October 28, 2005
Revised March 1, 2006
Accepted March 8, 2006

Article

Central core disease is due to RYR1 mutations in more than 90% of patients

Shiwen Wu 1, Carlos A. Ibarra M 1, May Christine V. Malicdan 1, Kumiko Murayama 1, Yasuko Ichihara 2, Hirosato Kikuchi 3, Ikuya Nonaka 1, Satoru Noguchi 1, Yukiko K. Hayashi 1, and Ichizo Nishino 1 *

1 Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Japan
2 Department of Anesthesiology, Tokyo Rinkai Hospital, Tokyo, Japan
3 Department of Anesthesiology, Saitama Medical School, Saitama, Japan

* To whom correspondence should be addressed.
Ichizo Nishino, E-mail: nishino{at}ncnp.go.jp


  Abstract

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 {alpha}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.

Keywords: central core disease; genotype-phenotype correlation; muscular dystrophy; myopathy; ryanodine receptor 1 mutations.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Anesth. Analg.Home page
W. Klingler, H. Rueffert, F. Lehmann-Horn, T. Girard, and P. M. Hopkins
Core Myopathies and Risk of Malignant Hyperthermia
Anesth. Analg., October 1, 2009; 109(4): 1167 - 1173.
[Abstract] [Full Text] [PDF]

Home page
 Br J AnaesthHome page
M. Broman, A. Gehrig, G. Islander, M. Bodelsson, E. Ranklev-Twetman, H. Ruffert, and C. R. Muller
Mutation screening of the RYR1-cDNA from peripheral B-lymphocytes in 15 Swedish malignant hyperthermia index cases
Br. J. Anaesth., May 1, 2009; 102(5): 642 - 649.
[Abstract] [Full Text] [PDF]

Home page
 NeurologyHome page
L. Morrison
Unraveling RYR1 mutations and muscle biopsies
Neurology, January 8, 2008; 70(2): 99 - 100.
[Full Text] [PDF]

Home page
 NeurologyHome page
I. Sato, S. Wu, M. C. A. Ibarra, Y. K. Hayashi, H. Fujita, M. Tojo, S. J. Oh, I. Nonaka, S. Noguchi, and I. Nishino
Congenital neuromuscular disease with uniform type 1 fiber and RYR1 mutation
Neurology, January 8, 2008; 70(2): 114 - 122.
[Abstract] [Full Text] [PDF]

Home page
 BrainHome page
H. Zhou, H. Jungbluth, C. A. Sewry, L. Feng, E. Bertini, K. Bushby, V. Straub, H. Roper, M. R. Rose, M. Brockington, et al.
Molecular mechanisms and phenotypic variation in RYR1-related congenital myopathies
Brain, August 1, 2007; 130(8): 2024 - 2036.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.