Human Molecular Genetics Advance Access originally published online on August 29, 2006
Human Molecular Genetics 2006 15(18):2791-2803; doi:10.1093/hmg/ddl221
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Characterization of recessive RYR1 mutations in core myopathies
1 The Dubowitz Neuromuscular Centre, Imperial College, Hammersmith Hospital, London W120NN, UK, 2 Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599-7260, USA, 3 Centre for Inherited Neuromuscular Disorders, Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Trust, Oswestry SY10 7AG, UK, 4 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 and 7 Departments of Anaesthesia and Research, Basel University Hospital, 4031 Basel, Switzerland
* To whom correspondence should be addressed at: Departments of Anesthesia and Research, Basel University Hospital, Hebelstrasse 20, 4031 Basel, Switzerland. Tel: +41 61 265 2373; Fax: +41 61 265 3702; Email: susan.treves{at}unibas.ch
Received July 14, 2006; Accepted August 3, 2006
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, whereas 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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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