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**, and
Gerald R.
Crabtree§§¶¶
From the §§ Howard Hughes Medical Institute and the
Departments of ¶¶ Developmental Biology and
Pathology, Beckman Center for Molecular and
Genetic Medicine, Stanford University, Stanford, California 94305, the
¶ Laboratory of Neurochemistry, National Institute for Mental
Health, Bethesda, Maryland 20892, and the ** Samuel Lunenfeld
Research Institute, Mount Sinai Hospital,
Toronto, Ontario M5G 1X5, Canada
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 HNF1
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 HNF1 null mice, which are diabetic. DCoH function as it pertains
to HNF1 activity appears to be partially complemented by a newly
identified homolog, DCoH2.
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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