The mutated human gene encoding hepatocyte nuclear factor 1 beta inhibits kidney formation in developing Xenopus embryos

The transcription factor hepatocyte nuclear factor 1 beta (HNF1 beta) is a tissue-specific regulator that also plays an essential role in early develo pment of vertebrates. In humans, four heterozygous mutations in the HNF1 be ta gene have been identified that lead to early onset of diabetes and sever e primary renal defects. The degree and type of renal defects seem to depen d on the specific mutation. We show that the frameshift mutant P328L329fsde lCCTCT associated with nephron agenesis retains its DNA-binding properties and acts as a gain-of-function mutation with increased transactivation pote ntial in transfection experiments. Expression of this mutated factor in the Xenopus embryo leads to defective development and agenesis of the pronephr os, the first kidney form of amphibians. Very similar defects are generated by overexpressing in Xenopus the wild-type HNF1 beta, which is consistent with the gain-of-function property of the mutant. In contrast, introduction of the human HNF1 beta mutant R137-K161del, which is associated with a red uced number of nephrons with hypertrophy of the remaining ones and which ha s an impaired DNA binding, shows only a minor effect on pronephros developm ent in Xenopus. Thus, the overexpression of both human mutants has a differ ent effect on renal development in Xenopus, reflecting the variation in ren al phenotype seen with these mutations. We conclude that mutations in human HNF1 beta can be functionally characterized in Xenopus. Our findings imply that HNF1 beta not only is an early marker of kidney development but also is functionally involved in morphogenetic events, and these processes can b e investigated in lower vertebrates.