title: Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I.
abstract: Hereditary tyrosinaemia type I, a severe autosomal recessive metabolic disease, affects the liver and kidneys and is caused by deficiency of fumarylacetoacetate hydrolase (FAH). Mice homozygous for a FAH gene disruption have a neonatal lethal phenotype caused by liver dysfunction and do not represent an adequate model of the human disease. Here we demonstrate that treatment of affected animals with 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3-cyclohexanedione abolished neonatal lethality, corrected liver function and partially normalized the altered expression pattern of hepatic mRNAs. The prolonged lifespan of affected animals resulted in a phenotype analogous to human tyrosinaemia type I including hepatocellular carcinoma. The adult FAH-/- mouse will serve as useful model for studies of the pathophysiology and treatment of hereditary tyrosinaemia type I as well as hepatic cancer.
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health Sciences University, Portland 97201, USA.
authors.forename: M
authors.initials: M
authors.lastname: Grompe
authors.forename: S
authors.initials: S
authors.lastname: Lindstedt
authors.forename: M
authors.initials: M
authors.lastname: al-Dhalimy
authors.forename: N G
authors.initials: NG
authors.lastname: Kennaway
authors.forename: J
authors.initials: J
authors.lastname: Papaconstantinou
authors.forename: C A
authors.initials: CA
authors.lastname: Torres-Ramos
authors.forename: C N
authors.initials: CN
authors.lastname: Ou
authors.forename: M
authors.initials: M
authors.lastname: Finegold
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000596:Amino Acids / Q000097:blood; D000818:Animals; D003512:Cyclohexanones / Q000627:therapeutic use* / Q000633:toxicity; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use* / Q000633:toxicity; D005260:Female; D006537:Heptanoates / Q000378:metabolism; D006801:Humans; D006867:Hydrolases / Q000172:deficiency; D008099:Liver / Q000187:drug effects / Q000648:ultrastructure; D008107:Liver Diseases / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009579:Nitrobenzoates / Q000627:therapeutic use* / Q000633:toxicity; D010179:Pancreas / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D014443:Tyrosine / Q000097:blood*; D000509:alpha-Fetoproteins / Q000378:metabolism
chemical_list: D000596:Amino Acids; D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D006537:Heptanoates; D009579:Nitrobenzoates; D012333:RNA, Messenger; D000509:alpha-Fetoproteins; D014443:Tyrosine; C020804:succinylacetone; D006867:Hydrolases; C020156:fumarylacetoacetase; C077073:nitisinone