Clinical Presentation and Molecular Pathophysiology of Autosomal Dominant Hemochromatosis Caused by a Novel Ferroportin Mutation
Clinical Presentation and Molecular Pathophysiology of Autosomal Dominant Hemochromatosis Caused by a Novel Ferroportin Mutation
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DOI：
10.1002/hep.23377
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发表时间：
2010-03-01
期刊：
影响因子：
13.5
通讯作者：
Cox, Timothy M.
中科院分区：
文献类型：
--
作者：
Griffiths, William J. H.;Mayr, Roman;Cox, Timothy M.
编码铁转运蛋白的SLC40A1基因突变与常染色体显性血色素沉着症有关。铁转运蛋白被hepcidin直接抑制，hepcidin是一种关键的铁调节肽，SLC40A1突变的功能后果解释了在铁转运蛋白疾病患者中观察到的表型差异。我们描述了一个具有新的SLC40A1突变的大谱系，并通过体外分析阐明了铁过载的相关分子机制。SLC40A1基因的整个编码序列在一个家系中测序，表现为常染色体显性高铁蛋白血症。通过在人胚胎肾细胞中过表达野生型和突变型铁转运蛋白融合蛋白，研究了一种新的SLC40A1突变的功能影响。用铁转运法研究这些细胞的铁输出；用共聚焦显微镜观察运铁蛋白的亚细胞定位。一种新的SLC40A1突变p.R489K分离与铁超载在一个家庭巨噬细胞型铁转运蛋白病的临床和组织病理学征象。过表达p.R489K运铁蛋白的人胚胎肾细胞与过表达运铁蛋白的野生型细胞相比，铁输出能力下降。亚细胞定位研究表明，p.R489K铁转运蛋白在细胞内异常保留。结论：我们报道了一种新的病理性SLC40A1变异，该变异与细胞内突变蛋白保留导致的铁转运蛋白细胞表面异常表达有关。这些发现预测巨噬细胞型铁转运蛋白疾病，在该亲属中观察到表型。研究运铁蛋白及其突变体的分子细胞生物学是理解这种日益被认识的血色素沉着病发病机制的关键，这种疾病对常规治疗反应不佳。(肝脏病学51:788 2010;795)。
Mutations in the SLC40A1 gene, which encodes ferroportin, are associated with autosomal dominant hemochromatosis. Ferroportin is inhibited directly by hepcidin, a key iron-regulatory peptide, and functional consequences of SLC40A1 mutations account for observed phenotypic differences in patients with ferroportin disease. We describe a large pedigree with a novel SLC40A1 mutation and, through in vitro analysis, elucidate the associated molecular mechanism of iron overload. The entire coding sequence of the SLC40A1 gene was sequenced in a pedigree, presenting with autosomal dominant hyperferritinemia. The functional effects of a novel SLC40A1 mutation were studied by overexpression of wild-type and mutant ferroportin fusion proteins in human embryonic kidney cells. Iron export was studied in these cells using (59)Fe transport assays; subcellular localization of ferroportin was examined by way of confocal microscopy. A novel SLC40A1 mutation p.R489K segregated with iron overload in a family with clinical and histopathological signs of macrophage-type ferroportin disease. Human embryonic kidney cells overexpressing p.R489K ferroportin showed decreased iron export capacity when compared with wild-type ferroportin overexpressing cells. Subcellular localization studies demonstrated that p.R489K ferroportin was retained abnormally within an intracellular compartment. Conclusion: We report a novel pathological SLC40A1 variant associated with abnormal cell surface expression of ferroportin due to intracellular retention of the mutant protein. These findings predict macrophage-type ferroportin disease, the phenotype observed in this kindred. Study of the molecular cell biology of ferroportin and its mutants is key to understanding the pathogenesis of this increasingly recognized form of hemochromatosis, which responds poorly to conventional therapy. (HEPATOLOGY 2010;51:788-795.)