Characterization of recessive RYR1 mutations in core myopathies

Zhou, Haiyan and Yamaguchi, Naohiro and Xu, Le and Wang, Ying and Sewry, Caroline and Jungbluth, Heinz and Zorzato, Francesco and Bertini, Enrico and Muntoni, Francesco and Meissner, Gerhard and Treves, Susan. (2006) Characterization of recessive RYR1 mutations in core myopathies. Human Molecular Genetics, 15 (18). pp. 2791-2803.

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Official URL: http://edoc.unibas.ch/dok/A6174314

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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.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Perioperative Patient Safety (Girard/Treves)
UniBasel Contributors:Treves, Susan
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Oxford University Press
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:15 May 2017 08:30
Deposited On:25 Oct 2013 08:33

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