Keratin 8 Y54H and G62C mutations are not associated with liver disease
Keratin 8 Y54H and G62C mutations are not associated with liver disease
复制标题
角蛋白 8 Y54H 和 G62C 突变与肝病无关
作者：
J. Halangk;T. Berg;G. Puhl;T. Mueller;R. Nickel;A. Kage;O. Landt;W. Luck;B. Wiedenmann;P. Neuhaus;H. Witt
细胞骨架由三个丝状系统组成：微丝、中间丝和微管。在上皮细胞中，I型角蛋白如角蛋白18(KRT18)和II型角蛋白如角蛋白8(KRT8)聚合形成中间纤维。KRT18和KRT8是在包括肝脏和胰腺在内的胃肠道单层上皮细胞中表达的主要角蛋白。
动物研究表明，KRT8和KRT18对机械和毒性损伤具有保护作用。2.高表达突变型KRT18的转基因小鼠表现出脆弱的肝细胞，细胞骨架丝中断。3这些小鼠与野生型KRT18相比，患上慢性肝炎，更容易受到肝损伤。4 KRT8缺失小鼠的生存能力取决于不同品系的小鼠的遗传背景，提示进一步的遗传因素对所产生的表型有贡献。例如，在一个小鼠品系中，KRT8缺陷小鼠因广泛的肝脏出血而在胚胎发育过程中死亡。5然而，在另一个品系中，55%的KRT8缺陷小鼠的预期寿命是正常的，但却出现了炎症性肠病的症状，在某些情况下还出现了肝脏的轻微炎症。这些发现支持胚胎外缺陷对这些胚胎的致死性负责。7此外，KRT8基因缺失的小鼠表现出异常的肝脏结构，与野生型小鼠相比，暴露于肝脏有毒物质后更容易受到肝脏损伤。
上述结果支持角蛋白突变可能使人类患肝病的假设。事实上，Ku等人描述了两个KRT8突变和隐源性肝硬变之间的联系。在密码子62(G62C)处发现了一个涉及甘氨酸到半胱氨酸的杂合性单碱基替换…
The cytoskeleton comprises three filamentous systems: microfilaments, intermediate filaments, and microtubules. In epithelial cells, type I keratins such as keratin 18 (KRT18) and type II keratins such as keratin 8 (KRT8) polymerise to form the intermediate filaments. KRT18 and KRT8 represent the major keratins expressed in single-layered epithelia of the gastrointestinal tract including liver and pancreas.1
Animal studies suggest KRT8 and KRT18 have a hepatoprotective role against mechanical and toxic injury.2 Transgenic mice overexpressing mutant KRT18 display fragile hepatocytes with disrupted cytoskeleton filaments.3 These mice developed chronic hepatitis and were more susceptible to liver injury in comparison to mice overexpressing wild type KRT18.4 The viability of KRT8 null mice depends on the genetic background of the different mouse strains suggesting further genetic factors contribute to the resultant phenotype. For instance, in one mouse strain KRT8 -deficient mice died during embryonic development due to extensive liver haemorrhage.5 However, in another strain 55% of the KRT8 -deficient mice had a normal life expectancy but developed signs of inflammatory bowel disease and in some cases a mild inflammation of the liver.6 A recent report emphasises the importance of Keratin 8 for the formation of an intact placental barrier function for the viability of KRT8 -deficient embryos. These findings argue in favour of an extraembryonic defect responsible for lethality of these embryos.7 Furthermore, KRT8 null mice showed an abnormal histological liver architecture and were more vulnerable to liver damage after exposure to hepatotoxic substances compared to wild type mice.8–10
The above mentioned results support the hypothesis that keratin mutations might predispose humans to liver disease. Indeed, Ku et al described an association between two KRT8 mutations and cryptogenic cirrhosis. A heterozygous single base substitution involving a Gly to Cys at codon 62 (G62C) was found …
维持肝细胞完整性需要简单的上皮角蛋白。
DOI：
--
发表时间：
1997
期刊：
The American journal of pathology
影响因子：
--
作者：
Loranger,A;Duclos,S;Grenier,A;Price,J;Wilson-Heiner,M;Baribault,H;Marceau,N
通讯作者：
Marceau,N
影响因子：
15.9
作者：
Ku, NO;Michie, SA;Omary, MB
通讯作者：
Omary, MB
影响因子：
10.5
作者：
BARIBAULT, H;PRICE, J;OSHIMA, RG
通讯作者：
OSHIMA, RG