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

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.