首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >X-linked cholestasis in mouse due to mutations of the P4-ATPase ATP11C
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X-linked cholestasis in mouse due to mutations of the P4-ATPase ATP11C

机译:P4-ATPase ATP11C突变导致小鼠X连锁性胆汁淤积

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摘要

Transporters at the hepatic canalicular membrane are essential for the formation of bile and the prevention of cholestatic liver disease. One such example is ATP8B1, a P4-type ATPase disrupted in three inherited forms of intrahepatic cholestasis. Mutation of the X-linked mouse gene Atp11c, which encodes a paralogous P4-type ATPase, precludes B-cell development in the adult bone marrow, but also causes hyperbilirubinemia. Here we explore this hyperbilirubinemia in two independent Atp11c mutant mouse lines, and find that it originates from an effect on nonhemato-poietic cells. Liver function tests and histology revealed only minor pathology, although cholic acid was elevated in the serum of mutant mice, and became toxic to mutant mice when given as a dietary supplement. The majority of homozygous mutant females also died of dystocia in a maternal genotype-specific manner. ATP11C therefore represents a multifunctional transporter, essential for adult B-cell development, the prevention of intrahepatic cholestasis, and parturition, and is a new candidate for genetically undiagnosed cases of cholestasis and dystocia in humans.
机译:肝小管膜上的转运蛋白对于形成胆汁和预防胆汁淤积性肝病至关重要。一个这样的例子是ATP8B1,这是一种在肝内胆汁淤积症的三种遗传形式中被破坏的P4型ATPase。 X链接的小鼠基因Atp11c的突变编码一种旁系的P4型ATPase,它阻止了成年骨髓中B细胞的发育,但也会引起高胆红素血症。在这里,我们在两个独立的Atp11c突变小鼠系中探索了这种高胆红素血症,发现它源于对非造血细胞的影响。肝功能测试和组织学检查仅显示了轻微的病理变化,尽管胆汁酸在突变小鼠的血清中升高,并且当作为膳食补充剂使用时对突变小鼠具有毒性。大多数纯合突变女性也以母体基因型特异性方式死于难产。因此,ATP11C代表着一种多功能转运蛋白,对于成人B细胞的发育,肝内胆汁淤积的预防和分娩是必不可少的,并且是遗传上未经诊断的人类胆汁淤积和难产病例的新候选者。

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