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 M ethods) is critical for development of the pancreas in mice and is a k ey factor for the regulation of the insulin gene in the beta-cells of the endocrine pancreas(1-6). Targeted disruption of the Ipf1 gene enco ding IPF1 in transgenic mice results in a failure of the pancreas to d evelop (pancreatic agenesis)(4,7). 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 homoz ygous for the point deletion, whereas both parents are heterozygotes f or the same mutation. The deletion was not found in 184 chromosomes fr om 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 t he homeodomain essential for DNA binding, Expression of mutant IPF1 in Cos-1 cells confirms the expression of a prematurely terminated trunc ated protein of 16 kD. Thus, the affected patient should have no funct ional IPF1 protein. Given the essential role of IPF1 in pancreas devel opment, it is likely that this autosomal recessive mutation is the cau se of the pancreatic agenesis phenotype in this patient. Thus, IPF1 ap pears to be a critical regulator of pancreas development in humans as well as mice.