Allerson C R, Cazzola M, Rouault T A
Cell Biology and Metabolism Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Biol Chem. 1999 Sep 10;274(37):26439-47. doi: 10.1074/jbc.274.37.26439.
Hereditary hyperferritinemia-cataract syndrome (HHCS) is a novel genetic disorder characterized by elevated serum ferritin and early onset cataract formation. The excessive ferritin production in HHCS patients arises from aberrant regulation of L-ferritin translation caused by mutations within the iron-responsive element (IRE) of the L-ferritin transcript. IREs serve as binding sites for iron regulatory proteins (IRPs), iron-sensing proteins that regulate ferritin translation. Previous observations suggested that each unique HHCS mutation conferred a characteristic degree of hyperferritinemia and cataract severity in affected individuals. Here we have measured the in vitro affinity of the IRPs for the mutant IREs and correlated decreases in binding affinity with clinical severity. Thermodynamic analysis of these IREs has also revealed that although some HHCS mutations lead to changes in the stability and secondary structure of the IRE, others appear to disrupt IRP-IRE recognition with minimal effect on IRE stability. HHCS is a noteworthy example of a human genetic disorder that arises from mutations within a protein-binding site of an mRNA cis-acting element. Analysis of the effects of these mutations on the energetics of the RNA-protein interaction explains the phenotypic variabilities of the disease state.
遗传性高铁蛋白血症 - 白内障综合征（HHCS）是一种新型遗传性疾病，其特征为血清铁蛋白升高和早期白内障形成。HHCS患者体内铁蛋白过度产生源于L - 铁蛋白转录本中铁反应元件（IRE）内的突变导致L - 铁蛋白翻译的异常调控。IRE作为铁调节蛋白（IRP）的结合位点，IRP是调节铁蛋白翻译的铁感应蛋白。先前的观察表明，每个独特的HHCS突变在受影响个体中赋予了特征性程度的高铁蛋白血症和白内障严重程度。在这里，我们测量了IRP对突变IRE的体外亲和力，并将结合亲和力的降低与临床严重程度相关联。对这些IRE的热力学分析还表明，虽然一些HHCS突变导致IRE稳定性和二级结构的变化，但其他突变似乎破坏了IRP - IRE识别，对IRE稳定性影响最小。HHCS是一种值得注意的人类遗传疾病实例，它源于mRNA顺式作用元件的蛋白质结合位点内的突变。分析这些突变对RNA - 蛋白质相互作用能量学的影响解释了疾病状态的表型变异性。
