Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance
Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance
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DOI：
10.1016/j.ajhg.2007.12.012
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发表时间：
2008-03-01
影响因子：
9.8
通讯作者：
Hallers, Ronald G.
中科院分区：
文献类型：
--
作者：
Mochel, Fanny;Knight, Melanie A.;Hallers, Ronald G.
在瑞典北部的患者中描述了一种伴有严重运动不耐受和肌红蛋白尿的肌病，骨骼肌中伴有琥珀酸脱氢酶和乌头碱酶的缺乏。我们确定了铁硫簇支架蛋白ISCU基因作为该疾病患者共享纯合子区域内的候选基因。我们发现ISCU的单一突变可能会加强弱剪接受体位点，从而导致外显子保留。患者肌肉中ISCU mRNA和线粒体ISCU蛋白的显著减少与骨骼肌中铁调节蛋白IRP1的减少和细胞内铁超载有关，这与该疾病中铁稳态的肌肉特异性改变相一致。ISCU在铁硫簇生物合成中与弗里德赖希共济失调基因产物fraataxin相互作用。因此，我们的研究结果扩展了已知的由铁硫簇生物发生缺陷引起的人类疾病的范围。
A myopathy with severe exercise intolerance and myoglobinuria has been described in patients from northern Sweden, with associated deficiencies of succinate dehydrogenase and aconitase in skeletal muscle. We identified the gene for the iron-sulfur cluster scaffold protein ISCU as a candidate within a region of shared homozygosity among patients with this disease. We found a single mutation in ISCU that likely strengthens a weak splice acceptor site, with consequent exon retention. A marked reduction of ISCU mRNA and mitochondrial ISCU protein in patient muscle was associated with a decrease in the iron regulatory protein IRP1 and intracellular iron overload in skeletal muscle, consistent with a muscle-specific alteration of iron homeostasis in this disease. ISCU interacts with the Friedreich ataxia gene product frataxin in iron-sulfur cluster biosynthesis. Our results therefore extend the range of known human diseases that are caused by defects in iron-sulfur cluster biogenesis.