In a female infant with pancreatic agenesis (PAGEN1; 260370), Schwitzgebel et al. (2003) identified compound heterozygosity for 2 missense mutations in exon 2 of the IPF1 gene: a 319G-T transversion resulting in a glu164-to-asp (E164D) substitution, and a 359G-A transition resulting in a glu178-to-lys (E178K; 600733.0009) substitution, both at highly conserved residues within helices 1 and 2, respectively, of the homeodomain. Her parents, who had high normal fasting glucose levels but no glucose intolerance, were each heterozygous for 1 of the mutations; a maternal uncle who had type 2 diabetes (T2D; 125853) was heterozygous for E164D. Both mutants decreased the protein half-life significantly, leading to intracellular IPF1 levels of 36% and 27% of wildtype levels. Both mutant proteins were translocated normally to the nucleus, and their DNA-binding activity on different known target promoters was similar to that of wildtype protein. However, transcriptional activity of both mutant IPF1 proteins, alone or in combination with FOXA2 (600288), PBX1 (176310), or the heterodimer E47-beta-2 (see 147141) was reduced, findings accounted for by decreased IPF1 steady-state levels and not by impaired protein-protein interactions. The authors concluded that IPF1 level is critical for human pancreas formation.
