Hyperphenylalaninemia and impaired glucose tolerance in mice lacking the bifunctional DCoH gene

J Henri Bayle; Filippo Randazzo; Georg Johnen; Seymour Kaufman; Andras Nagy; Janet Rossant; Gerald R Crabtree

doi:10.1074/jbc.M201983200

Hyperphenylalaninemia and impaired glucose tolerance in mice lacking the bifunctional DCoH gene

J Biol Chem. 2002 Aug 9;277(32):28884-91. doi: 10.1074/jbc.M201983200. Epub 2002 May 13.

Authors

J Henri Bayle¹, Filippo Randazzo, Georg Johnen, Seymour Kaufman, Andras Nagy, Janet Rossant, Gerald R Crabtree

Affiliation

¹ Howard Hughes Medical Institute and the Department Pathology, Beckman Center for Molecular and Genetic Medicine, Stanford University, Stanford, California 94305, USA.

PMID: 12011081
DOI: 10.1074/jbc.M201983200

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.

Publication types

Research Support, U.S. Gov't, P.H.S.

MeSH terms

Alleles
Amino Acid Sequence
Animals
Blotting, Northern
Blotting, Western
Cataract / genetics
Cell Nucleus / metabolism
DNA / metabolism
DNA-Binding Proteins*
Dimerization
Electroporation
Gene Deletion
Genetic Complementation Test
Glucose / metabolism
Glucose Intolerance / genetics*
Hepatocyte Nuclear Factor 1
Hepatocyte Nuclear Factor 1-alpha
Hepatocyte Nuclear Factor 1-beta
Humans
Hydro-Lyases / genetics*
Liver / metabolism
Mice
Mice, Knockout
Models, Molecular
Molecular Sequence Data
Mutation
Nuclear Proteins*
Phenylketonurias / genetics*
Phenylketonurias / pathology
Sequence Homology, Amino Acid
Time Factors
Tissue Distribution
Transcription Factors / metabolism
Transcription, Genetic
Transcriptional Activation
Transfection

Substances

DNA-Binding Proteins
HNF1A protein, human
HNF1B protein, human
Hepatocyte Nuclear Factor 1-alpha
Hnf1a protein, mouse
Hnf1b protein, mouse
Nuclear Proteins
Transcription Factors
Hepatocyte Nuclear Factor 1
Hepatocyte Nuclear Factor 1-beta
DNA
Hydro-Lyases
pterin-4a-carbinolamine dehydratase
Glucose