Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence

Abstract

The homeodomain protein IPF1 (also known as IDX1, STF1 and PDX1; see Methods) is critical for development of the pancreas in mice and is a key factor for the regulation of the insulin gene in the beta-cells of the endocrine pancreas. Targeted disruption of the Ipf1 gene encoding IPF1 in transgenic mice results in a failure of the pancreas to develop (pancreatic agenesis). Here, we report the identification of a single nucleotide deletion within codon 63 of the human IPF1 gene (13q12.1) in a patient with pancreatic agenesis. The patient is homozygous for the point deletion, whereas both parents are heterozygotes for the same mutation. The deletion was not found in 184 chromosomes from normal individuals, indicating that the mutation is unlikely to be a rare polymorphism. The point deletion causes a frame shift at the C-terminal border of the transactivation domain of IPF1 resulting in the translation of 59 novel codons before termination, aminoproximal to the homeodomain essential for DNA binding. Expression of mutant IPF1 in Cos-1 cells confirms the expression of a prematurely terminated truncated protein of 16 kD. Thus, the affected patient should have no functional IPF1 protein. Given the essential role of IPF1 in pancreas development, it is likely that this autosomal recessive mutation is the cause of the pancreatic agenesis phenotype in this patient. Thus, IPF1 appears to be a critical regulator of pancreas development in humans as well as mice.

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.…”

Paternal insulin resistance and its association with umbilical cord insulin concentrations

“…Severe fetal mutations that greatly alter insulin secretion, or insulin action, such as those associated with pancreatic agenesis or mutations in the glucokinase gene leading to MODY, considerably alter birthweight [12][13][14]. Although these mutations are rare, they have established the principle that fetal genes can alter insulin-mediated growth.…”

Stable and functional regeneration of pancreatic beta-cell population in nSTZ-rats treated with tungstate

“…In recent years, major advances in our understanding of pancreas embryogenesis have led to the identification of several transcription factors that are involved in this process [3]. Among these, PDX-1 plays a critical role in the development of the pancreas, since mutations in this gene result in pancreatic agenesis in both mice and humans [4,5]. Moreover, studies on the dynamics of the adult pancreas have shown that adult beta cells adjust their mass to distinct metabolic states that occur during the life span, such as pregnancy [6] or obesity [7,8].…”