Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 34, Pages 12485-12490Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0806015105
Keywords
congenital myopathy; disease model; intracellular calcium release
Categories
Funding
- National Research Service Award Predoctoral National Institutes of Health fellowship
- postdoctoral National Institutes of Health fellowship [T32 NS07493]
- Muscular Dystrophy Association
- University of Utah Catalyst Grant Research Program
- NS Science Foundation of Ireland [RFP2007/BCIF165]
- National Institute of Arthritis and Musculoskeletal and Skin Diseases [RO1-AR-48911]
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Mutations affecting the seemingly unrelated gene products, SepN1, a selenoprotein of unknown function, and RyR1, the major component of the ryanodine receptor intracellular calcium release channel, result in an overlapping spectrum of congenital myopathies. To identify the immediate developmental and molecular roles of SepN and RyR in vivo, loss-of-function effects were analyzed in the zebrafish embryo. These studies demonstrate the two proteins are required for the same cellular differentiation events and are needed for normal calcium fluxes in the embryo. SepN is physically associated with RyRs and functions as a modifier of the RyR channel. In the absence of SepN, ryanodine receptors from zebrafish embryos or human diseased muscle have altered biochemical properties and have lost their normal sensitivity to redox conditions, which likely accounts for why mutations affecting either factor lead to similar diseases.
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