title: Distinct molecular and morphogenetic properties of mutations in the human HNF1beta gene that lead to defective kidney development.
abstract: The homeobox transcription factor hepatocyte nuclear factor 1beta (HNF1beta) is a tissue-specific regulator that plays an essential role in early vertebrate development. In humans, heterozygous mutations in the HNF1beta gene are associated with young-onset diabetes as well as a variety of disorders of renal development with cysts as the most consistent feature. This report compares and classifies nine different HNF1beta mutations that lead in humans to distinct renal diseases, including solitary functioning kidney, renal dysplasia, glomerulocystic kidney disease, and oligomeganephronia. Analysis of these mutants in vitro identifies mutants that either retain or lack DNA binding. Investigation of the transactivation potential in transfected cell lines reveals a strict correlation between DNA binding and transactivation. Introduction of these mutants into developing Xenopus embryos shows that these mutants interfere with pronephros development, the first kidney form in amphibian. Whereas three mutants lead in Xenopus to a reduction or agenesis of the pronephric tubules and the anterior part of the duct, six mutants generate an enlargement of the pronephric structures. The differential morphogenetic potential in the developing embryo does not strictly correlate with the properties observed in vitro or in transfected cell lines. This suggests that the functional test in the developing embryo defines features of the HNF1beta protein that cannot be assessed in cell cultures. The distinct properties observed in the various HNF1beta mutants may guide the classification of the phenotypes observed in patients with a mutated HNF1beta gene.
authors.affiliation: Institut für Zellbiologie, Universitätsklinikum Essen, Essen, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bohn
authors.forename: Heike
authors.initials: H
authors.lastname: Thomas
authors.forename: Gülüzar
authors.initials: G
authors.lastname: Turan
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.forename: Coralie
authors.initials: C
authors.lastname: Bingham
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: Gerhart U
authors.initials: GU
authors.lastname: Ryffel
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000378:metabolism; D004625:Embryo, Nonmammalian; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000002:abnormalities* / Q000196:embryology*; D008164:Luminescent Proteins / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation; D014162:Transfection; D014981:Xenopus; D029867:Xenopus Proteins
chemical_list: D004268:DNA-Binding Proteins; C496495:HNF1B protein, human; C000627649:Hnf1b protein, Xenopus; D008164:Luminescent Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D029867:Xenopus Proteins; D051539:Hepatocyte Nuclear Factor 1-beta; D049452:Green Fluorescent Proteins; D004247:DNA