Endo F, Sun M S
Department of Pediatrics, Kumamoto University, Japan.
J Inherit Metab Dis. 2002 May;25(3):227-34. doi: 10.1023/a:1015646400182.
Hereditary tyrosinaemia type I (HT 1) (McKusick 276700) is caused by a deficiency of fumarylacetoacetate hydrolase (FAH) activity, the last enzyme in the tyrosine catabolic pathway. Homozygous disruption of the gene encoding FAH in mice (Fah) causes neonatal lethality (i.e. lethal Albino deletion c14CoS mice), which limits the use of this animal as a model for HT I. We developed a new mouse model that carries two genetic defects, Fah and 4-hydroxyphenylpyruvate dioxygenase (Hpd). The double mutant Fah -/- Hpd -/- mice grew normally without evidence of liver and renal disease, showing a phenotype similar to Hpd -/- mice. Complete blockage of the tyrosine catabolic pathway at the, step of HPD prevents development of clinical phenotypes. Administration of homogentisate resulted in rapid apoptosis of hepatocytes and renal tubular epithelial cells, a central feature of visceral injury in patients with HT I. Simultaneously, renal tubular function was impaired, resulting in Fanconi syndrome. Apoptosis of hepatocyte and renal tubular cells is prevented by the caspase inhibitors YVAD or DEVD. However, these inhibitors do not prevent the release of cytochrome c or the development of renal tubular dysfunction. Apoptosis of hepatocytes and of renal tubular epithelial cells are characteristic features of this disease and the apoptotic signal in this disease seems to be initiated by fumarylacetoacetate.
遗传性I型酪氨酸血症（HT 1）（麦库西克编号276700）是由于酪氨酸分解代谢途径中的最后一种酶——富马酰乙酰乙酸水解酶（FAH）活性缺乏所致。在小鼠中编码FAH的基因（Fah）的纯合缺失会导致新生儿死亡（即致死性白化缺失c14CoS小鼠），这限制了该动物作为HT I模型的应用。我们开发了一种携带两种遗传缺陷的新小鼠模型，即Fah和4-羟基苯丙酮酸双加氧酶（Hpd）。双突变Fah -/- Hpd -/-小鼠正常生长，没有肝脏和肾脏疾病的迹象，表现出与Hpd -/-小鼠相似的表型。在HPD步骤酪氨酸分解代谢途径的完全阻断可防止临床表型的发展。给予尿黑酸会导致肝细胞和肾小管上皮细胞迅速凋亡，这是HT I患者内脏损伤的一个主要特征。同时，肾小管功能受损，导致范科尼综合征。半胱天冬酶抑制剂YVAD或DEVD可防止肝细胞和肾小管细胞凋亡。然而，这些抑制剂并不能阻止细胞色素c的释放或肾小管功能障碍的发展。肝细胞和肾小管上皮细胞凋亡是这种疾病的特征性表现，并且这种疾病中的凋亡信号似乎是由富马酰乙酰乙酸引发的。
