HEPATOCYTE NUCLEAR FACTOR-1 INACTIVATION RESULTS IN HEPATIC-DYSFUNCTION, PHENYLKETONURIA, AND RENAL FANCONI SYNDROME

HNF1 is a transcriptional activator of many hepatic genes including al bumin, alpha 1-antitrypsin, and alpha- and beta-fibrinogen. It is rela ted to the homeobox gene family and is predominantly expressed in live r and kidney. Mice lacking HNF1 fail to thrive and die around weaning after a progressive wasting syndrome with a marked liver enlargement. The transcription rate of genes like albumin and alpha 1-antitrypsin i s reduced, while the gene coding for phenylalanine hydroxylase is tota lly silent, giving rise to phenylketonuria. Mutant mice also suffer fr om severe Fanconi syndrome caused by renal proximal tubular dysfunctio n. The resulting massive urinary glucose loss leads to energy and wate r wasting. HNF1-deficient mice may provide a model for human renal Fan coni syndrome.