LOSS OF FUMARYLACETOACETATE HYDROLASE IS RESPONSIBLE FOR THE NEONATAL HEPATIC-DYSFUNCTION PHENOTYPE OF LETHAL ALBINO MICE
LOSS OF FUMARYLACETOACETATE HYDROLASE IS RESPONSIBLE FOR THE NEONATAL HEPATIC-DYSFUNCTION PHENOTYPE OF LETHAL ALBINO MICE
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DOI：
10.1101/gad.7.12a.2298
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发表时间：
1993-12-01
影响因子：
10.5
通讯作者：
SORIANO, P
中科院分区：
文献类型：
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作者：
GROMPE, M;ALDHALIMY, M;SORIANO, P
c14CoS 白化基因缺失纯合子小鼠在新生儿时因肝功能障碍而死亡。先前的图谱研究已将此缺陷与编码肝细胞特异性发育调节位点 (alf/hsdr-1) 的 310 kb 片段相关联。编码富马酰乙酰乙酸水解酶 (Fah) 的基因（一种催化酪氨酸分解代谢最后一步的代谢酶）也映射到相同的缺失区间。为了测试白化缺失突变体中发现的新生儿缺陷是否归因于 Fah 的缺失，而不是归因于与缺失相对应的另一个基因，我们通过胚胎干细胞中的基因靶向产生了 Fah 突变小鼠。 Fah缺陷小鼠在出生后12小时内因低血糖和肝功能障碍而死亡。此外，在受影响的动物中也发现了与白化缺失突变体相同的肝脏 mRNA 表达改变模式。我们得出的结论是，alf/hsdr-1 缺失的新生儿致死和肝功能障碍表型完全归因于 Fah 的丢失。
Mice homozygous for the c14CoS albino deletion die as neonates as a result of liver dysfunction. Previous mapping studies have associated this defect with a 310-kb fragment encoding the hepatocyte-specific developmental regulation locus (alf/hsdr-1). The gene encoding fumarylacetoacetate hydrolase (Fah), a metabolic enzyme that catalyzes the last step of tyrosine catabolism, also maps to the same deletion interval. To test whether the neonatal defects found in the albino deletion mutants are attributable to loss of Fah, and not to another gene mapping to the deletion, we have generated Fah mutant mice by gene targeting in embryonic stem cells. Fah-deficient mice die within 12 hr after birth from hypoglycemia and liver dysfunction. In addition, the same pattern of altered liver mRNA expression found in the albino deletion mutants was also found in affected animals . We conclude that the neonatal lethal and liver dysfunction phenotype of the alf/hsdr-1 deletion is entirely attributable to loss of Fah.