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Human Molecular Genetics, 2003, Vol. 12, No. 4 379-388
© 2003 Oxford University Press

Clinical and functional effects of a deletion in a COOH-terminal lumenal loop of the skeletal muscle ryanodine receptor

Francesco Zorzato1,2, Naohiro Yamaguchi3, Le Xu3, Gerhard Meissner3, Clemens R. Müller4, Pierre Pouliquin2, Francesco Muntoni5, Caroline Sewry5, Thierry Girard1 and Susan Treves1,*

1Departments für Anaesthesie und Forschung, Kantonsspital Basel, 4031 Basel, Switzerland, 2Dipartimento di Medicina Sperimentale e Diagnostica, Università di Ferrara, 44100 Ferrara, Italy, 3Departments of Biochemistry and Biophysics and Molecular and Cellular Physiology, University of North Carolina, Chapel Hill, NC 27599-7260, USA, 4Institut für Humangenetik, Biozentrum der Universität Würzburg, 97074 Würzburg, Germany and 5The Dubowitz Neuromuscular Centre, Imperial College School of Medicine, London W12 0NN, UK

Received October 25, 2002; Accepted December 3, 2002

We have identified a patient affected by a relatively severe form of central core disease (CCD), carrying a heterozygous deletion (amino acids 4863–4869) in the pore-forming region of the sarcoplasmic reticulum calcium release channel. The functional effect of this deletion was investigated (i) in lymphoblastoid cells from the affected patient and her mother, who was also found to harbour the mutation and (ii) in HEK293 cells expressing recombinant mutant channels. Lymphoblastoid cells carrying the RYR1 deletion exhibit an ‘unprompted’ calcium release from intracellular stores, resulting in significantly smaller thapsigargin-sensitive intracellular Ca2+ stores, compared with lymphoblastoid cells from control individuals. Blocking the RYR1 with dantrolene restored the intracellular calcium stores to levels similar to those found in control cells. Single channel and [3H]ryanodine binding measurements of heterologously expressed mutant channels revealed a reduced ion conductance and loss of ryanodine binding and regulation by Ca2+. Heterologous expression of recombinant RYR1 peptides and analysis of their membrane topology demonstrate that the deleted amino acids are localized in the lumenal loop connecting membrane-spanning segments M8 and M10. We provide evidence that a deletion in the lumenal loop of RYR1alters channel function and causes CCD.

* To whom correspondence should be addressed at: ZLF Basel Kantonsspital, Lab 408, Hebelstrasse 20, 4031 Basel, Switzerland. Tel: +41 612652373; Fax: +41 612653702; Email: susan.treves{at}unibas.ch


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