title: Hyperphenylalaninemia and impaired glucose tolerance in mice lacking the bifunctional DCoH gene.
abstract: The bifunctional protein DCoH (Dimerizing Cofactor for HNF1) acts as an enzyme in intermediary metabolism and as a binding partner of the HNF1 family of transcriptional activators. HNF1 proteins direct the expression of a variety of genes in the liver, kidney, pancreas, and gut and are critical to the regulation of glucose homeostasis. Mutations of the HNF1alpha gene underlie maturity onset diabetes of the young (MODY3) in humans. DCoH acts as a cofactor for HNF1 that stabilizes the dimeric HNF1 complex. DCoH also catalyzes the recycling of tetrahydrobiopterin, a cofactor of aromatic amino acid hydroxylases. To examine the roles of DCoH, a targeted deletion allele of the murine DCoH gene was created. Mice lacking DCoH are viable and fertile but display hyperphenylalaninemia and a predisposition to cataract formation. Surprisingly, HNF1 function in DCoH null mice is only slightly impaired, and mice are mildly glucose-intolerant in contrast to HNF1alpha null mice, which are diabetic. DCoH function as it pertains to HNF1 activity appears to be partially complemented by a newly identified homolog, DCoH2.
authors: Howard Hughes Medical Institute and the Department Pathology, Beckman Center for Molecular and Genetic Medicine, Stanford University, Stanford, California 94305, USA.
authors: J Henri
authors: JH
authors: Bayle
authors: Filippo
authors: F
authors: Randazzo
authors: Georg
authors: G
authors: Johnen
authors: Seymour
authors: S
authors: Kaufman
authors: Andras
authors: A
authors: Nagy
authors: Janet
authors: J
authors: Rossant
authors: Gerald R
authors: GR
authors: Crabtree
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002386:Cataract / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins; D019281:Dimerization; D018274:Electroporation; D017353:Gene Deletion; D005816:Genetic Complementation Test; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000235:genetics*; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D006836:Hydro-Lyases / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins; D010661:Phenylketonurias / Q000235:genetics* / Q000473:pathology; D017386:Sequence Homology, Amino Acid; D013997:Time Factors; D014018:Tissue Distribution; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C496496:Hnf1b protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D004247:DNA; D006836:Hydro-Lyases; C076392:pterin-4a-carbinolamine dehydratase; D005947:Glucose