Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis
Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis
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DOI：
10.1038/ng1274
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发表时间：
2004-01-01
期刊：
影响因子：
30.8
通讯作者：
Goldberg, YP
中科院分区：
文献类型：
--
作者：
Papanikolaou, G;Samuels, ME;Goldberg, YP
青少年血色素沉着症是一种早发型常染色体隐性遗传性铁超负荷疾病，可导致心肌病、糖尿病和性腺功能减退，发生于青少年和20岁出头。1、2）。青少年血色素沉着症以前曾与染色体1 q的着丝粒区有关（参考文献10）。3 6），在人类基因组组装中不完整的区域。在这里，我们报告的位置克隆的基因座与青少年血色素沉着症和鉴定的一个新的基因至关重要的铁代谢。我们精细地绘制了希腊血统家族中的重组间隔，并在以前未知功能的转录单位（LOC 148738）中发现了多个有害突变，现在称为HFE 2，其蛋白质产物我们称为hemojuvelin。对希腊、加拿大和法国家族的分析表明，在所有三个群体中观察到一种突变，即氨基酸取代G320 V，占所发现突变的三分之二。HFE 2转录物表达限于肝脏、心脏和骨骼肌，类似于铁调素，一种涉及铁代谢的关键蛋白（7-9）。青少年血色素沉着症患者尿铁调素水平降低，表明血幼素可能不是铁调素受体。相反，HFE 2似乎调节铁调素表达。
Juvenile hemochromatosis is an early-onset autosomal recessive disorder of iron overload resulting in cardiomyopathy, diabetes and hypogonadism that presents in the teens and early 20s (refs. 1,2). Juvenile hemochromatosis has previously been linked to the centromeric region of chromosome 1q (refs. 3 6), a region that is incomplete in the human genome assembly. Here we report the positional cloning of the locus associated with juvenile hemochromatosis and the identification of a new gene crucial to iron metabolism. We finely mapped the recombinant interval in families of Greek descent and identified multiple deleterious mutations in a transcription unit of previously unknown function (LOC148738), now called HFE2, whose protein product we call hemojuvelin. Analysis of Greek, Canadian and French families indicated that one mutation, the amino acid substitution G320V, was observed in all three populations and accounted for two-thirds of the mutations found. HFE2 transcript expression was restricted to liver, heart and skeletal muscle, similar to that of hepcidin, a key protein implicated in iron metabolism(7-9). Urinary hepcidin levels were depressed in individuals with juvenile hemochromatosis, suggesting that hemojuvelin is probably not the hepcidin receptor. Rather, HFE2 seems to modulate hepcidin expression.