Jurynec Michael J, Xia Ruohong, Mackrill John J, Gunther Derrick, Crawford Thomas, Flanigan Kevin M, Abramson Jonathan J, Howard Michael T, Grunwald David Jonah
Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA.
Proc Natl Acad Sci U S A. 2008 Aug 26;105(34):12485-90. doi: 10.1073/pnas.0806015105. Epub 2008 Aug 19.
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.
影响看似不相关的基因产物SepN1(一种功能未知的硒蛋白)和兰尼碱受体细胞内钙释放通道的主要成分RyR1的突变,会导致一系列重叠的先天性肌病。为了确定SepN和RyR在体内的直接发育和分子作用,我们在斑马鱼胚胎中分析了功能丧失效应。这些研究表明,这两种蛋白质对于相同的细胞分化事件是必需的,并且是胚胎正常钙通量所必需的。SepN与RyRs物理结合,并作为RyR通道的调节剂发挥作用。在没有SepN的情况下,斑马鱼胚胎或人类患病肌肉中的兰尼碱受体具有改变的生化特性,并且失去了对氧化还原条件的正常敏感性,这可能解释了为什么影响这两个因素的突变会导致相似的疾病。