Fulltext

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

Zorzato, Francesco ; Yamaguchi, Naohiro ; Xu, Le ; Meissner, Gerhard ; Müller, Clemens R. ; Pouliquin, Pierre ; Muntoni, Francesco ; Sewry, Caroline ; Girard, Thierry ; Treves, Susan

In: Human Molecular Genetics, 2003, vol. 12, no. 4, p. 379-388

Zum persönliche Liste hinzufügen
    Titel
    • Clinical and functional effects of a deletion in a COOH-terminal lumenal loop of the skeletal muscle ryanodine receptor
    Autor
    • Zorzato, Francesco. Departments für Anaesthesie und Forschung, Kantonsspital Basel, 4031 Basel, Switzerland
    • Yamaguchi, Naohiro. Departments of Biochemistry and Biophysics and Molecular and Cellular Physiology, University of North Carolina, Chapel Hill, NC 27599-7260, USA
    • Xu, Le. Departments of Biochemistry and Biophysics and Molecular and Cellular Physiology, University of North Carolina, Chapel Hill, NC 27599-7260, USA
    • Meissner, Gerhard. Departments of Biochemistry and Biophysics and Molecular and Cellular Physiology, University of North Carolina, Chapel Hill, NC 27599-7260, USA
    • Müller, Clemens R.. Institut für Humangenetik, Biozentrum der Universität Würzburg, 97074 Würzburg, Germany and
    • Pouliquin, Pierre. Dipartimento di Medicina Sperimentale e Diagnostica, Università di Ferrara, 44100 Ferrara, Italy
    • Muntoni, Francesco. The Dubowitz Neuromuscular Centre, Imperial College School of Medicine, London W12 0NN, UK
    • Sewry, Caroline. The Dubowitz Neuromuscular Centre, Imperial College School of Medicine, London W12 0NN, UK
    • Girard, Thierry. Departments für Anaesthesie und Forschung, Kantonsspital Basel, 4031 Basel, Switzerland
    • Treves, Susan. Departments für Anaesthesie und Forschung, Kantonsspital Basel, 4031 Basel, Switzerland
    Dokumententyp
    • Postprint
    Sprache
    • Englisch
    Veröffentlicht in
    • Human Molecular Genetics, 2003, vol. 12, no. 4, p. 379-388. Oxford University Press
    Andere elektronische Ausgabe
    Klassifikation
    • Gesundheit
    OAI-PMH-ID
    • oai:doc.rero.ch:291260
    Summary
    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