title: The Caenorhabditis elegans K10C2.4 gene encodes a member of the fumarylacetoacetate hydrolase family: a Caenorhabditis elegans model of type I tyrosinemia.
abstract: In eukaryotes and many bacteria, tyrosine is degraded to produce energy via a five-step tyrosine degradation pathway. Mutations affecting the tyrosine degradation pathway are also of medical importance as mutations affecting enzymes in the pathway are responsible for type I, type II, and type III tyrosinemia. The most severe of these is type I tyrosinemia, which is caused by mutations affecting the last enzyme in the pathway, fumarylacetoacetate hydrolase (FAH). So far, tyrosine degradation in the nematode Caenorhabditis elegans has not been studied; however, genes predicted to encode enzymes in this pathway have been identified in several microarray, proteomic, and RNA interference (RNAi) screens as perhaps being involved in aging and the control of protein folding. We sought to identify and characterize the genes in the worm tyrosine degradation pathway as an initial step in understanding these findings. Here we describe the characterization of the K10C2.4, which encodes a homolog of FAH. RNAi directed against K10C2.4 produces a lethal phenotype consisting of death in young adulthood, extensive damage to the intestine, impaired fertility, and activation of oxidative stress and endoplasmic stress response pathways. This phenotype is due to alterations in tyrosine metabolism as increases in dietary tyrosine enhance it, and inhibition of upstream enzymes in tyrosine degradation with RNAi or genetic mutations reduces the phenotype. We also use our model to identify genes that suppress the damage produced by K10C2.4 RNAi in a pilot genetic screen. Our results establish worms as a model for the study of type I tyrosinemia.
authors.affiliation: Department of Medicine, Division of Geriatric Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA. fishera@dom.pitt.edu
authors.forename: Alfred L
authors.initials: AL
authors.lastname: Fisher
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Page
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Lithgow
authors.forename: Lindsey
authors.initials: L
authors.lastname: Nash
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017173:Caenorhabditis elegans / Q000201:enzymology* / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005298:Fertility / Q000235:genetics; D006867:Hydrolases / Q000235:genetics / Q000378:metabolism*; D007422:Intestines / Q000201:enzymology* / Q000473:pathology; D009154:Mutation; D018384:Oxidative Stress / Q000235:genetics; D010641:Phenotype; D017510:Protein Folding; D034622:RNA Interference; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism*; D020176:Tyrosinemias / Q000201:enzymology* / Q000235:genetics / Q000473:pathology
chemical_list: D029742:Caenorhabditis elegans Proteins; D014443:Tyrosine; D006867:Hydrolases; C020156:fumarylacetoacetase