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.

Downregulation of pancreatic-duodenal homeobox 1 expression in breast cancer patients: A mechanism of proliferation and apoptosis in cancer

“…The pancreatic-duodenal homeobox protein 1 (PDX-1) is 6 kb in length and located on chromosome 5 in mice, 12 in rats and 13q12.1 in humans (1). During mouse embryogenesis, PDX-1 is expressed in the pancreas, duodenum and gastric pyloric glands.…”

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

“…In this regard, the importance of Pdx1 in the pancreas is emphasized by the near-absence of pancreas formation in Pdx1-null mice [12][13][14]. This dramatic phenotype also occurs in humans with homozygous mutations of the human ortholog of the Pdx1 gene (known as Ipf1) [15,16], thereby underscoring the relevance of this factor to human pancreas development. Pdx1 also appears to be crucial for the function of the mature β cell.…”

Genome sequence of a diabetes-prone rodent reveals a mutation hotspot around the ParaHox gene cluster

“…For example, targeted deletion in mice causes loss of pancreas and anterior duodenum and is lethal (9,17). In humans, pancreatic agenesis has been reported in a patient with a homozygous frameshift mutation before the Pdx1 homeobox and in a compound heterozygous patient with substitution mutations in helices 1 and 2 of the homeodomain (18)(19)(20).…”