Keratin 8 and 18 mutations are risk factors for developing liver disease of multiple etiologies
Keratin 8 and 18 mutations are risk factors for developing liver disease of multiple etiologies
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DOI：
10.1073/pnas.0936165100
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发表时间：
2003-05-13
影响因子：
11.1
通讯作者：
Omary, MB
中科院分区：
文献类型：
--
作者：
Ku, NO;Darling, JM;Omary, MB
在隐源性肝硬化患者中发现了角蛋白8和18（K8/K18）突变，但角蛋白突变在非隐源性肝硬化中的作用以及普通人群中角蛋白突变的发生率尚不清楚。我们从314例非隐源性肝硬化患者和349例血库志愿者的肝组织中分离基因组DNA，筛选K8/K18突变。在11例独立的胆道闭锁、B/C型肝炎、酒精、原发性胆汁性肝硬化和暴发性肝炎患者中发现了7个独特的K8/K18突变。11例患者中有7例具有先前在隐源性肝硬化患者中描述的突变：K8 Tyr-53 -> His，K8 Gly-61 -> Cys和K18 His-127 -> Leu。其余4名患者在一个K8和其他三个K18新位点发生突变。在349个血库对照样本中，只有一个样本含有Tyr-53 His突变，一个样本含有Gly-61 -> Cys K8突变（当比较肝硬化与对照组时，P < 0.004）。在肝病和血库组中发现了两个额外的突变，因此可能代表多态性。肝角蛋白突变的细胞质丝状沉积物是不太常见的肝脏没有突变（P = 0.03）。因此，K8/K18可能是发展隐源性和非隐源性肝病形式的易感基因。
Keratin 8 and 18 (K8/K18) mutations are found in patients with cryptogenic cirrhosis, but the role of keratin mutations in noncryptogenic cirrhosis and the incidence of keratin mutations in the general population are not known. We screened for K8/K18 mutations in genomic DNA isolated from 314 liver explants of patients who primarily had noncryptogenic cirrhosis, and from 349 blood bank volunteers. Seven unique K8/K18 mutations were found in 11 independent patients with biliary atresia, hepatitis B/C, alcohol, primary biliary cirrhosis, and fulminant hepatitis. Seven of the 11 patients had mutations previously described in patients with cryptogenic cirrhosis: K8 Tyr-53 --> His, K8 Gly-61 --> Cys, and K18 His-127 --> Leu. The four remaining patients had mutations at one K8 and three other K18 new sites. Of the 349 blood bank control samples, only one contained the Tyr-53 His and one the Gly-61 --> Cys K8 mutations (P < 0.004 when comparing cirrhosis versus control groups). Two additional mutations were found in both the liver disease and blood bank groups and, hence, likely represent polymorphisms. Livers with keratin mutations had cytoplasmic filamentous deposits that were less frequent in livers without the mutations (P = 0.03). Therefore, K8/K18 are likely susceptibility genes for developing cryptogenic and noncryptogenic forms of liver disease.