Jl. Aponte et al., Point mutations in the murine fumarylacetoacetate hydrolase gene: Animal models for the human genetic disorder hereditary tyrosinemia type 1, P NAS US, 98(2), 2001, pp. 641-645
Citations number
40
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Hereditary tyrosinemia type 1 (HT1) is a severe autosomal recessive metabol
ic disease associated with point mutations in the human fumarylacetoacetate
hydrolase (FAH) gene that disrupt tyrosine catabolism. An acute form of HT
1 results in death during the first months of life because of hepatic failu
re, whereas a chronic form leads to gradual development of liver disease of
ten accompanied by renal dysfunction, childhood rickets, neurological crisi
s, and hepatocellular carcinoma. Mice homozygous for certain chromosome 7 d
eletions of the albino Tyr; c locus that also include Fah die perinatally a
s a result of liver dysfunction and exhibit a complex syndrome characterize
d by structural abnormalities and alterations in gene expression in the liv
er and kidney. Here we report that two independent, postnatally lethal muta
tions induced by N-ethyl-N-nitrosourea and mapped near Tyr are alleles of F
ah. 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 t
he resulting mRNA, and a severe reduction of Fah mRNA levels. increased lev
els of the diagnostic metabolite succinylacetone in the urine of the Fah(62
87SB) and Fah(5961SB) mutants indicate that these mutations cause a decreas
e in Fah enzymatic activity. Thus, the neonatal phenotype present in both m
utants is due to a deficiency in Fah caused by a point mutation, and we pro
pose Fah(5961SB) and Fah(6287SB) as mouse models for acute and chronic form
s of human HT1, respectively.