In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 98, No. 2 ( 2001-01-16), p. 641-645
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.98.2.641
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2001
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
Permalink