Selenoprotein N is required for ryanodine receptor calcium release channel activity in human and zebrafish muscle.
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.
Jurynec
Michael J
MJ
Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA.
Xia
Ruohong
R
Mackrill
John J
JJ
Gunther
Derrick
D
Crawford
Thomas
T
Flanigan
Kevin M
KM
Abramson
Jonathan J
JJ
Howard
Michael T
MT
Grunwald
David Jonah
DJ
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D002648:Child; D004198:Disease Susceptibility; D004625:Embryo, Nonmammalian; D005260:Female; D006801:Humans; D008969:Molecular Sequence Data; D024510:Muscle Development; D018657:Muscle Fibers, Slow-Twitch; D009124:Muscle Proteins / Q000502:physiology*; D009132:Muscles / Q000166:cytology / Q000378:metabolism*; D009135:Muscular Diseases; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism* / Q000502:physiology; D051140:Selenoproteins / Q000502:physiology*; D015027:Zebrafish
D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; C435489:SELENON protein, human; D051140:Selenoproteins; D002118:Calcium