Brain Advance Access originally published online on May 4, 2007
Brain 2007 130(8):2024-2036; doi:10.1093/brain/awm096
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Molecular mechanisms and phenotypic variation in RYR1-related congenital myopathies
1Dubowitz Neuromuscular Centre, Imperial College, Hammersmith Hospital, London W12 0NN, UK, 2Department of Paediatric Neurology, Evelina Children's Hospital, St Thomas’ Hospital, London SE1 7EH, UK, 3Centre for Inherited Neuromuscular Disorders, Robert Jones & Agnes Hunt Orthopaedic Hospital, Oswestry, UK, 4Unit of Molecular Medicine, Ospedale Bambino Gesù, Rome, Italy, 5Institute for Human Genetics, International Centre for Life, University of Newcastle upon Tyne, Newcastle upon Tyne, UK, 6Department of Paediatrics, Birmingham Heartlands Hospital, UK, 7Department of Neurology, King's College Hospital, London, UK, 8Alder Hey Children's Hospital, Liverpool, UK, 9Department of Neurosciences, Psychiatry and Anaesthesiology, University of Messina, Messina, Italy, 10Department of Neurology, The Royal London Hospital, London, UK, 11Institute für Humangenetik, Universität Würzburg, Biozentrum am Hubland, Germany and 12Departments of Anaesthesia and Research, Basel University Hospital, 4031 Basel, Switzerland
Correspondence to: Professor Francesco Muntoni, Dubowitz Neuromuscular Centre, Imperial College, Hammersmith Hospital, Du Cane Road, London W12 0NN. E-mail: f.muntoni{at}imperial.ac.uk
Dominant mutations in the skeletal muscle ryanodine receptor (RYR1) gene are well-recognized causes of both malignant hyperthermia susceptibility (MHS) and central core disease (CCD). More recently, recessive RYR1 mutations have been described in few congenital myopathy patients with variable pathology, including multi-minicores. Although a clinical overlap between patients with dominant and recessive RYR1 mutations exists, in most cases with recessive mutations the pattern of muscle weakness is remarkably different from that observed in dominant CCD.
In order to characterize the spectrum of congenital myopathies associated with RYR1 mutations, we have investigated a cohort of 44 patients from 28 families with clinical and/or histopathological features suggestive of RYR1 involvement. We have identified 25 RYR1 mutations, 9 of them novel, including 12 dominant and 13 recessive mutations. With only one exception, dominant mutations were associated with a CCD phenotype, prominent cores and predominantly occurred in the RYR1 C-terminal exons 101 and 102. In contrast, the 13 recessive RYR1 mutations were distributed evenly along the entire RYR1 gene and were associated with a wide range of clinico-pathological phenotypes.
Protein expression studies in nine cases suggested a correlation between specific mutations, RyR1 protein levels and resulting phenotype: in particular, whilst patients with dominant or recessive mutations associated with typical CCD phenotypes appeared to have normal RyR1 expression, individuals with more generalized weakness, multi-minicores and external ophthalmoplegia had a pronounced depletion of the RyR1 protein. The phenomenon of protein depletion was observed in some patients compound heterozygous for recessive mutations at the genomic level and silenced another allele in skeletal muscle, providing additional information on the mechanism of disease in these patients.
Our data represent the most extensive study of RYR1-related myopathies and indicate complex genotype-phenotype correlations associated with mutations differentially affecting assembly and function of the RyR1 calcium release channel.
Key Words: skeletal muscle ryanodine receptor gene (RYR1); central core disease (CCD); multi-minicore disease (MmD); genotype–phenotype correlations
Abbreviations: CCD, central core disease; CNM, centronuclear myopathy; MHS, malignant hyperthermia susceptibility; MmD, multi-minicore disease; RYR1, skeletal muscle ryanodine receptor gene; SEPN1, selenoprotein N gene
.
Received December 22, 2006. Revised March 23, 2007. Accepted March 28, 2007.
*These authors contributed equally to this work.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  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]
|
|
|
|
 |
|
 B. T. Corona, C. Rouviere, S. L. Hamilton, and C. P. Ingalls Eccentric contractions do not induce rhabdomyolysis in malignant hyperthermia susceptible mice J Appl Physiol, November 1, 2008; 105(5): 1542 - 1553. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Jurynec, R. Xia, J. J. Mackrill, D. Gunther, T. Crawford, K. M. Flanigan, J. J. Abramson, M. T. Howard, and D. J. Grunwald Selenoprotein N is required for ryanodine receptor calcium release channel activity in human and zebrafish muscle PNAS, August 26, 2008; 105(34): 12485 - 12490. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. L. Diaz-Sylvester, M. Porta, and J. A. Copello Halothane modulation of skeletal muscle ryanodine receptors: dependence on Ca2+, Mg2+, and ATP Am J Physiol Cell Physiol, April 1, 2008; 294(4): C1103 - C1112. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Xu, Y. Wang, N. Yamaguchi, D. A. Pasek, and G. Meissner Single Channel Properties of Heterotetrameric Mutant RyR1 Ion Channels Linked to Core Myopathies J. Biol. Chem., March 7, 2008; 283(10): 6321 - 6329. [Abstract] [Full Text] [PDF]
|
|