Frequent mutation reversion inversely correlates with clinical severity in a genetic liver disease, hereditary tyrosinemia

Hereditary tyrosinemia type I (HTI), a severe disease affecting primarily the liver, is caused by a deficiency of fumarylacetoacetate hydrolase (FAH). HTI is clinically heterogeneous, with no correlation between genotype and phenotype. Reversion of FAH mutant alleles in livers of HTI patients was reported previously, but the clinical significance of this phenomenon has not been fully documented. In the present study, the mosaic expression of FAH was analyzed by immune cytochemistry in liver specimens from a cohort of 26 French-Canadian HTI patients who underwent liver transplantation and related to the histopathologic status of the liver and the clinical history. Reversion was observed in 88% of patients with reverted surfaces ranging from 0.1% to 85%. Patients with the chronic form had a much higher surface of reversion (average, 36%) than those with the acute form (average, 1.6%) and a lower incidence of liver dysplasia. Within reverted nodules, hepatocytes had a normal appearance and showed no dysplasia. Hepatocellular carcinoma was observed only in FAH-negative regions. In summary, the extent of mutation reversion of the FAH gene in the liver of HTI patients was inversely correlated with the clinical severity of the disease, suggesting that the corrected hepatocytes play a substantial protective role in liver function. (C) 2003 Elsevier Inc. All rights reserved.