Geographical and Ethnic Distribution of Mutations of the Fumarylacetoacetate Hydrolase Gene in Hereditary Tyrosinemia Type 1.

Hereditary tyrosinemia type 1 (HT1) (OMIM 276700) is a severe inherited metabolic disease affecting mainly hepatic and renal functions that leads to a fatal outcome if untreated. HT1 results from a deficiency of the last enzyme of tyrosine catabolism, fumarylacetoacetate hydrolase (FAH). Biochemical findings include elevated succinylacetone in blood and urine; elevated plasma concentrations of tyrosine, methionine and phenylalanine; and elevated tyrosine metabolites in urine. The HT1 frequency worldwide is about 1 in 100,000 individuals. In some areas, where the incidence of HT1 is noticeably higher, prevalence of characteristic mutations has been reported, and the estimated incidence of carriers of a specific mutation can be as high as 1 out of 14 adults. Because the global occurrence of HT1 is relatively low, a considerable number of cases may go unrecognized, underlining the importance to establish efficient prenatal and carrier testing to facilitate an early detection of the disease. Here we describe the 95 mutations reported so far in HT1 with special emphasis on their geographical and ethnic distributions. Such information should enable the establishment of a preferential screening process for mutations most predominant in a given region or ethnic group.

Proteomic characterization of mouse cytosolic and membrane prostate fractions: high levels of free SUMO peptides are androgen-regulated.

The prostate is a relatively homogeneous tissue that is highly specialized in synthetic and secretory functions. The frequency of malignant growth explains its great clinical significance. We used here a combination of subcellular fractionation, 1-DE (one-dimensional gel electrophoresis) protein separation and mass spectrometry, to establish a prostate protein expression profile in mice. Analysis of proteins present in cytosolic (C) and membrane (P) prostate fractions led to the identification of 619 distinct proteins. A majority of abundant proteins were found to compose the metabolism and protein synthesis machinery. Those identified also correspond to known endoplasmic reticulum and Golgi residents, chaperones and anterograde cargos. They included a series of proteins involved in exocytic/endocytic trafficking. Among the signaling proteins, we identified the ubiquitin-like peptides smt3. We showed that both free small ubiquitin-related modifier SUMO-2/3 and SUMO-1 levels are subject to tight control by the androgen 5alpha-dihydrotestosterone (DHT). By contrast with SUMO-2/3, free SUMO-1 peptides are particularly abundant in the prostate when compared with other tissues. Therefore, we report prostate protein expression profiles of cytosolic and membrane fractions in mice. Our data suggest that the identified free SUMO peptides play an important role in this secretory tissue.

No evidence of maternal cell colonization in reverted liver nodules of tyrosinemia type I patients.

BACKGROUND AND AIMS: Hereditary tyrosinemia type I (HTI) is a recessively inherited disease caused by a deficiency of fumarylacetoacetate hydrolase (FAH), the last enzyme of the tyrosine catabolic pathway. The mosaic pattern of FAH expression observed in the livers of >85% of studied patients was shown to result from the correction of the mutation in one of the FAH alleles. Bilateral cell trafficking can occur between mother and fetus and such an event could be responsible for the chimerism observed in some diseases. It also has been reported that the liver repopulation observed in a HTI murine model by serial transplantation of bone marrow-derived cells was caused by a fusion of these cells to host hepatocytes. These observations led us to test the possibility that the transfer of nucleated heterozygous maternal cells in the fetal circulation could be responsible for the mosaic liver expression of FAH in HTI patients. METHODS: We used polymorphic markers of short cytosine-adenine DNA repeats to compare DNA from corrected liver sections of 4 HTI patients with DNA from their parents' blood. RESULTS: Genotyping showed that only one maternal allele is present in DNA isolated from FAH-expressing liver nodules of each proband for at least 1 marker. CONCLUSIONS: The corrected liver nodules in HTI patients are not of maternal origin and do not support cell trafficking and cell fusion as mechanisms of correction of the gene defect in hepatocytes of tyrosinemia patients.

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.