title: Agenesis of human pancreas due to decreased half-life of insulin promoter factor 1.
abstract: Neonatal diabetes mellitus can be transient or permanent. The severe form of permanent neonatal diabetes mellitus can be associated with pancreas agenesis. Normal pancreas development is controlled by a cascade of transcription factors, where insulin promoter factor 1 (IPF1) plays a crucial role. Here, we describe two novel mutations in the IPF1 gene leading to pancreas agenesis. Direct sequence analysis of exons 1 and 2 of the IPF1 gene revealed two point mutations within the homeobox in exon 2. Genetic analysis of the parents showed that each mutation was inherited from one parent. Mutations localized in helices 1 and 2, respectively, of the homeodomain, decreased the protein half-life significantly, leading to intracellular IPF1 levels of 36% and 27% of wild-type levels. Both mutant forms of IPF1 were normally translocated to the nucleus, and their DNA binding activity on different known target promoters was similar to that of the wild-type protein. However, transcriptional activity of both mutant IPF1 proteins, alone or in combination with HNF3 beta/Foxa2, Pbx1, or the heterodimer E47-beta 2 was reduced, findings accounted for by decreased IPF1 steady state levels and not by impaired protein-protein interactions. We conclude that the IPF1 level is critical for human pancreas formation.
authors.affiliation: Pediatric Endocrinology and Diabetology, Geneva University Hospital, CH-1211 Geneva, Switzerland. valerie.schwitzgebel@medcli.unige.ch
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Schwitzgebel
authors.forename: Aline
authors.initials: A
authors.lastname: Mamin
authors.forename: Thierry
authors.initials: T
authors.lastname: Brun
authors.forename: Beate
authors.initials: B
authors.lastname: Ritz-Laser
authors.forename: Maia
authors.initials: M
authors.lastname: Zaiko
authors.forename: Alexandre
authors.initials: A
authors.lastname: Maret
authors.forename: Francois R
authors.initials: FR
authors.lastname: Jornayvaz
authors.forename: Gerald E
authors.initials: GE
authors.lastname: Theintz
authors.forename: Olivier
authors.initials: O
authors.lastname: Michielin
authors.forename: Danielle
authors.initials: D
authors.lastname: Melloul
authors.forename: Jacques
authors.initials: J
authors.lastname: Philippe
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D006224:Cricetinae; D004247:DNA / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D017930:Genes, Reporter / Q000235:genetics; D005951:Glucose Tolerance Test; D049452:Green Fluorescent Proteins; D006207:Half-Life; D018398:Homeodomain Proteins; D006801:Humans; D007553:Isotope Labeling; D008164:Luminescent Proteins / Q000096:biosynthesis / Q000235:genetics; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009154:Mutation / Q000502:physiology*; D010179:Pancreas / Q000002:abnormalities* / Q000254:growth & development*; D010957:Plasmids / Q000235:genetics; D011233:Precipitin Tests; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D014162:Transfection; D014178:Translocation, Genetic / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; D008164:Luminescent Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D049452:Green Fluorescent Proteins; D004247:DNA