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Human Molecular Genetics Advance Access published online on August 29, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl221
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received July 14, 2006
Accepted August 3, 2006

Article

Characterization of recessive RYR1 mutations in core myopathies

Haiyan Zhou 1, Naohiro Yamaguchi 2, Le Xu 2, Ying Wang 2, Caroline Sewry 3, Heinz Jungbluth 4, Francesco Zorzato 5, Enrico Bertini 6, Francesco Muntoni 1, Gerhard Meissner 2, and Susan Treves 7 *

1 The Dubowitz Neuromuscular Centre, Imperial College, Hammersmith Hospital, London W120NN, U.K
2 Departments of Biochemistry and Biophysics and Molecular and Cellular Physiology, University of North Carolina, Chapel Hill, NC 27599-7260, USA
3 Centre for Inherited Neuromuscular Disorders, Robert Jones & Agnes Hunt Orthopaedic Hospital NHS Trust, Oswestry SY10 7AG, U.K
4 The Dubowitz Neuromuscular Centre, Imperial College, Hammersmith Hospital, London W120NN, U.K.; Department of Paediatric Neurology, Evelina Children's Hospital, St. Thomas' Hospital, London, UK
5 Dipartimento di Medicina Sperimentale e Diagnostica, Universita` di Ferrara, 44100 Ferrara, Italy
6 Unit of Molecular Medicine, Ospedale Bambin Gesu', Rome, Italy
7 Departments of Anaesthesia and Research, Basel University Hospital, Hebelstrasse 20, 4031 Basel, Switzerland

* To whom correspondence should be addressed.
Susan Treves, E-mail: susan.treves{at}unibas.ch


  Abstract

We have characterized at the molecular level, three families with core myopathies carrying apparent recessive mutations in their RYR1 gene and studied the pharmacological properties of myotubes carrying endogenous mutations as well as the properties of mutant channels expressed in HEK293 cells. The proband of family 1 carried p.Ala1577Thr + p.Gly2060Cys in trans, having inherited a mutation from each parent. Immunoblot analysis of proteins from the patient's skeletal muscle revealed low levels of ryanodine receptor (RyR1) but neither substitution alone or in combination affected the functional properties of RyR1 channels in a discernable way. Two affected siblings in family 2 carried p.Arg109Trp + p.Met485Val substitutions in cis, inherited from the unaffected father. Interestingly, both affected siblings only transcribed the mutated paternal allele in skeletal muscle, while the maternal allele was silent. Single channel measurements showed that recombinant, mutant RyR1 channels carrying both substitutions lost the ability to conduct Ca2 +. In this case as well, low levels of RyR1 were present in skeletal muscle extracts. The proband of family 3 carried p.Ser71Tyr + p.Asn2283His substitutions in trans. Recombinant channels with Asn2283His substitution showed an increased activity, whereas recombinant channels with p.Ser71Tyr + p.Asn2283His substitution lost activity upon isolation. Taken together, our data suggest major differences in the ways RYR1 mutations may affect patients with core myopathies, by compromising RyR1 protein expression, stability and/or activity.


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