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Agenesis of Human Pancreas due to Decreased Half-Life of Insulin Promoter Factor 1

Pediatric Endocrinology and Diabetology (V.M.S.) and Diabetes Unit (A.M., T.B., B.R.-L., M.Z., J.P.), Geneva University Hospital, CH-1211 Geneva, Switzerland; Pediatric Endocrinology and Diabetology, Lausanne University Hospital (A.M., F.R.J., G.E.T.), CH-1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research (O.M.) and Swiss Institute for Bioinformatics (O.M.), CH-1066 Epalinges, Switzerland; and Department of Endocrinology and Metabolism, Hebrew University Hadassah Medical Center (D.M.), 91120 Jerusalem, Israel

Address all correspondence and requests for reprints to: Dr. Valérie M. Schwitzgebel, Pediatric Endocrinology and Diabetology, Hôpital des Enfants, 6 rue Willy Donzé, CH-1211 Geneva, Switzerland. E-mail: valerie.schwitzgebel{at}medcli.unige.ch.

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 helixes 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 HNF3ß/Foxa2, Pbx1, or the heterodimer E47-ß2 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.

This work was supported by a grant from the Swiss National Science Foundation.

Abbreviations: aa, Amino acids; BHK, baby hamster kidney; CAT, chloramphenicol acetyl transferase; GFP, green fluorescent protein; GST, glutathione-S-transferase; HB-EGF, heparin-binding epidermal growth factor; HEK, human embryonic kidney; IPF1, insulin promoter factor 1; ND, neonatal diabetes mellitus; PAP, placental-alkaline phosphatase; PDX1, pancreatic duodenal homeobox factor 1.

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