Animal models reveal pathophysiologies of tyrosinemias.
The activity of the enzyme 4-hydroxyphenylpyruvic acid dioxygenase (HPD) is regulated by transcription factors. Mutations in the HPD locus are related to two known distinct diseases: hereditary tyrosinemia type 3 and hawkinsinuria. HPD-deficient mice are a good model with which to examine the biological effects of 4-hydroxyphenylpyruvic acid, which is a keto acid that causes no apparent visceral damage. In contrast, hereditary tyrosinemia type 1, a genetic disease caused by a deficiency of fumarylacetoacetate hydrolase (FAH), induces severe visceral injuries. Mice with FAH deficiency are lethal after birth; thus, efforts to elucidate the mechanisms of the disease process have been impeded. The use of Fah(-/-) Hpd(-/-) double-mutant mice has enabled studies on tyrosinemias, and essential features of visceral injury have been reveale.
Endo
Fumio
F
Department of Pediatrics, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan. fendo@gpo.kumamoto-u.ac.jp
Tanaka
Yasuhiko
Y
Tomoeda
Kaede
K
Tanoue
Akito
A
Tsujimoto
Gozoh
G
Nakamura
Kimitoshi
K
D015111:4-Hydroxyphenylpyruvate Dioxygenase / Q000172:deficiency / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D006713:Homogentisic Acid / Q000494:pharmacology; D006867:Hydrolases / Q000172:deficiency / Q000235:genetics; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D020176:Tyrosinemias / Q000201:enzymology*
D015111:4-Hydroxyphenylpyruvate Dioxygenase; D006867:Hydrolases; C020156:fumarylacetoacetase; D006713:Homogentisic Acid