Agenesis of human pancreas due to decreased half-life of insulin promoter factor 1

Article Article scientifique Article Agenesis of human pancreas due to decreased half-life of insulin promoter factor 1 eng 2003 author Schwitzgebel Luscher Valérie 133261 author Mamin Aline 133667 author Brun Thierry 0000-0002-1659-4283 24644 author Ritz Beate Andréa 96500 author Zaiko Maia 133738 author Maret Alexandre Gilbert André 65466 author Jornayvaz François 0000-0001-9425-3137 641037 author Theintz Gérald Edouard 26564 author Michielin Olivier author Melloul Danielle author Philippe Jacques 26481 4398-4406 10.1210/jc.2003-030046 12970316 0021-972X 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. Amino Acid Sequence Animals Blotting, Western Cells, Cultured Cricetinae DNA/genetics Electrophoretic Mobility Shift Assay Genes, Reporter/genetics Glucose Tolerance Test Green Fluorescent Proteins Half-Life Homeodomain Proteins Humans Isotope Labeling Luminescent Proteins/biosynthesis/genetics Molecular Sequence Data Mutagenesis Mutation/physiology Pancreas/abnormalities/growth & development Plasmids/genetics Precipitin Tests Reverse Transcriptase Polymerase Chain Reaction Trans-Activators/chemistry/genetics/metabolism Transcriptional Activation/genetics Transfection Translocation, Genetic/genetics Dewey 612 Dewey 616 Dewey 618 134 Département de physiologie cellulaire et métabolisme 21C 56 Département de médecine 221 58 Département de pédiatrie, gynécologie et obstétrique 223 false 144 Diabète et métabolisme 178 23 Diabète et régulation des gènes 36 The Journal of clinical endocrinology and metabolism 88 9 71632e25-b3fb-4301-be07-e61bf144428b Article (Published version) Restricted 4398-4406.pdf 394021 application/pdf restrictedAccess Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme Faculté de médecine / Section de médecine clinique / Département de médecine Faculté de médecine / Section de médecine clinique / Département de pédiatrie, gynécologie et obstétrique

Title	Published in	Access level	OA Policy	Year	Views	Downloads

Agenesis of human pancreas due to decreased half-life of insulin promoter factor 1	The Journal of clinical endocrinology and metabolism			2003	642	0

Archive ouverte UNIGE

Maret, Alexandre Gilbert André