一个中国遗传性血色病家系致病基因的突变分析

doi:10.3724/SP.J.1005.2014.1152

遗传 ›› 2014, Vol. 36 ›› Issue (11): 1152-1158.doi: 10.3724/SP.J.1005.2014.1152

一个中国遗传性血色病家系致病基因的突变分析

李元丰^{1, 3, 4}, 张红星^{1, 3, 4}, 张海涛^{1, 3, 4}, 彭晓波², 白丽丽², 贺福初^{1, 3, 4}, 邱泽武², 周钢桥^{1, 3, 4}

1. 中国人民解放军军事医学科学院放射与辐射医学研究所,北京蛋白质组研究中心,蛋白质组学国家重点实验室,北京 102206;
2. 中国人民解放军第三〇七医院中毒救治科,北京 100071;
3. 蛋白质药物国家工程研究中心,北京 102206;
4. 国家蛋白质科学中心(北京),北京 102206;

收稿日期:2014-05-26 出版日期:2014-11-20 发布日期:2014-10-28
通讯作者: 周钢桥,研究员,研究方向：医学遗传与基因组学。E-mail：zhougq114@gmail.com E-mail:E-mail：liyf_snp@163.com
作者简介:作者简介:李元丰,博士生,研究方向：医学遗传学。
基金资助:
国家杰出青年基金(编号：81125017),国家优秀青年基金(编号：81222027)和863项目(编号：2012AA02A205)资助

Mutation analysis of the pathogenic gene in a Chinese family with hereditary hemochromatosis

Yuanfeng Li^{1, 3, 4}, Hongxing Zhang^{1, 3, 4}, Haitao Zhang^{1, 3, 4}, Xiaobo Peng², Lili Bai², Fuchu He^{1, 3, 4}, Zewu Qiu², Gangqiao Zhou^{1, 3, 4}

1. State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, China;
2. Poisoning Treatment Department, No.307 Hospital of People’
s Liberation Army, Beijing 100071, China;
3. National Engineering Research Center for Protein Drugs, Beijing 102206, China;
4. National Center for Protein Sciences in Beijing, Beijing 102206, China

Received:2014-05-26 Online:2014-11-20 Published:2014-10-28

摘要/Abstract

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.G18C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。

关键词: 遗传性血色病, 基因, p.Q6H, p.C321X, 全外显子组测序

Abstract: Hereditary hemochromatosis (HHC) is a rare autosomal recessive disorder. We recruited a consanguineous Chinese family including the proband with HHC and other four members without HHC. Using whole-exome sequencing, we identified 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 absent 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 HJV can result in HHC, which will help genetic diagnosis and prenatal counseling for HHC.

Key words: hereditary hemochromatosis, p.Q6H, p.C321X, whole-exome sequencing

李元丰, 张红星, 张海涛, 彭晓波, 白丽丽, 贺福初, 邱泽武, 周钢桥. 一个中国遗传性血色病家系致病基因的突变分析[J]. 遗传, 2014, 36(11): 1152-1158.

Yuanfeng Li, Hongxing Zhang, Haitao Zhang, Xiaobo Peng, Lili Bai, Fuchu He, Zewu Qiu, Gangqiao Zhou. Mutation analysis of the pathogenic gene in a Chinese family with hereditary hemochromatosis[J]. HEREDITAS(Beijing), 2014, 36(11): 1152-1158.

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一个中国遗传性血色病家系致病基因的突变分析

Mutation analysis of the pathogenic gene in a Chinese family with hereditary hemochromatosis

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