一个中国遗传性血色病家系致病基因的突变分析-提交版课件.doc

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 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 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。我们招募了一个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，我们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HJV基上的纯合突变外，该者携带其它12个纯合突变危害性均不强。p.Q6H；p.C321X；全外显子组测序 Mutation analysis of the pathogenic gene in a Chinese family with hereditary hemochromatosis Yuanfeng Li1,3,4, Hongxing Zhang1,3,4, Haitao Zhang1,3,4, Xiaobo Peng2，Lili Bai2，Fuchu He1,3,4，Zewu Qiu2，Gangqiao Zhou1,3,4 1. State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206 2. Poisoning Treatment Department, No.307 Hospital of Peoples Liberation Army, Beijing 100071 3. National Engineering Research Center for Protein Drugs, Beijing 102206 4. National Center for Protein Sciences in Beijing, Beijing 102206 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 metaboli