中文摘要：

遗传性血色病（Hereditary hemochromatosis,HHC）是一种罕见的常染色体隐性遗传病.本课题组招募了一个HHC的近亲婚配家系,包括一名患HHC的先证者以及同一代的4名不患HHC的成员.通过对该HHC先证者进行全外显子组测序,在目前已知的与遗传性血色病相关的5个基因（HAMP、HJV、TFR2、FPN和HFE）中,发现在铁调素调节蛋白（Hemojuvelin,HJV）的编码基因HJV上存在两个纯合突变（c.G 18C和c.GC962_963AA）.其中,前者能够引起HJV蛋白发生p.Q6H的改变,但该突变的危害性较小,可能与血色病的发病无关;后者能够引起HJV蛋白发生p.C321X的改变,从而翻译出缺失糖基磷脂肌醇锚定结构域的截短型HJV蛋白.除了HJV基因上的纯合突变外,该先证者还携带了其他12个纯合突变,但这些突变的危害性均不强且其所在基因的功能与铁代谢无关.本实验室内部测序数据显示,在一般中国人群中不存在p.C321X突变,提示HJV基因上的p.C321X纯合突变可能是该HHC患者的致病性突变.与此相一致的是,4名不患HHC的家系成员中该位点为野生型纯合子或杂合子,均非p.C321X纯合子.文章首次报道了HJV p.C321X纯合突变可导致HHC,该结果将有助于遗传性血色病的基因诊断和产前咨询.

英文摘要：

Abstract： Hereditary hemochromatosis （HHC） is a rare autosomal recessive disorder. We recruited a consanguineous Chi- nese family including the proband with HHC and other four members without HHC. Using whole-exome sequencing, we iden- tified two homozygous mutations （c.G18C [p.Q6H] and c.GC962_963AA [p.C321X]） in the hemojuvelin gene （HJV） in the proband with HHC. No mutation was found in other four previously identified HHC related genes, HAMP, TFR2, FPN and HFE. The functional impact of p.Q6H mutation is weak whereas p.C321X, a premature termination mutation, results in a truncated HJV protein, which lacks the glycosylphosphatidylinositol （GPI） anchor domain. In addition to the mutations in HJV, other 12 homozygous mutations were identified in this patient. However, none of these mutations showed strong damaging impact and the mutated genes are not related to iron metabolism. Our in-house data further demonstrated that p.C321X is ab- sent in the general Chinese population, suggesting that the homozygous mutation p.C321X in HJV is causative in the patient with HHC. Accordingly, all of the four members without HHC from the same family carried wild-type alleles or heterozygous mutations, but not the homozygous mutation in this site. Thus, we found for the first time that the homozygous mutation p.C321X in HJVcan result in HHC, which will help genetic diagnosis and prenatal counseling for HHC.