Point mutations in the murine fumarylacetoacetate hydrolase gene: Animal models for the human genetic disorder hereditary tyrosinemia type 1
| Autor: | Gary A. Sega, Cymbeline T. Culiat, Eugene M. Rinchik, Loren Hauser, Catherine M. Withrow, Dabney K. Johnson, Jennifer L. Aponte, Madhu S Dhar, Donald A. Carpenter |
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| Rok vydání: | 2001 |
| Předmět: |
Male
Hydrolases Gene mutation Kidney Mice Exon Missense mutation Frameshift Mutation Mice Inbred BALB C Mice Inbred C3H Multidisciplinary Tyrosinemias Genetic disorder Exons Biological Sciences Heptanoates Liver Enzyme Induction Acute Disease Models Animal Fumarylacetoacetate hydrolase Female DNA Complementary RNA Splicing Molecular Sequence Data Mutation Missense Biology Frameshift mutation Tyrosinemia medicine Animals Humans Point Mutation RNA Messenger Alleles Crosses Genetic Base Sequence Point mutation medicine.disease Molecular biology Mice Mutant Strains Mice Inbred C57BL Amino Acid Substitution Animals Newborn Genes Mutagenesis Ethylnitrosourea Chronic Disease Genes Lethal Biomarkers |
| Zdroj: | Proceedings of the National Academy of Sciences. 98:641-645 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.98.2.641 |
| Popis: | Hereditary tyrosinemia type 1 (HT1) is a severe autosomal recessive metabolic disease associated with point mutations in the human fumarylacetoacetate hydrolase ( FAH ) gene that disrupt tyrosine catabolism. An acute form of HT1 results in death during the first months of life because of hepatic failure, whereas a chronic form leads to gradual development of liver disease often accompanied by renal dysfunction, childhood rickets, neurological crisis, and hepatocellular carcinoma. Mice homozygous for certain chromosome 7 deletions of the albino Tyr ; c locus that also include Fah die perinatally as a result of liver dysfunction and exhibit a complex syndrome characterized by structural abnormalities and alterations in gene expression in the liver and kidney. Here we report that two independent, postnatally lethal mutations induced by N -ethyl- N -nitrosourea and mapped near Tyr are alleles of Fah . The Fah 6287SB allele is a missense mutation in exon 6, and Fah 5961SB is a splice mutation causing loss of exon 7, a subsequent frameshift in the resulting mRNA, and a severe reduction of Fah mRNA levels. Increased levels of the diagnostic metabolite succinylacetone in the urine of the Fah 6287SB and Fah 5961SB mutants indicate that these mutations cause a decrease in Fah enzymatic activity. Thus, the neonatal phenotype present in both mutants is due to a deficiency in Fah caused by a point mutation, and we propose Fah 5961SB and Fah 6287SB as mouse models for acute and chronic forms of human HT1, respectively. |
| Databáze: | OpenAIRE |
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