Mutations in the proenteropeptidase gene are the molecular cause of congenital enteropeptidase deficiency

Enteropeptidase (enterokinase [E.C.3.4.21.9]) is a serine protease of the i ntestinal brush border in the proximal small intestine. It activates the pa ncreatic proenzyme trypsinogen, which, in turn, releases active digestive e nzymes from their inactive pancreatic precursors. Congenital enteropeptidas e deficiency is a rare recessively inherited disorder leading, in affected infants, to severe failure to thrive. The genomic structure of the proenter opeptidase gene (25 exons, total gene size 88 kb) was characterized in orde r to perform DNA sequencing in three clinically and biochemically proved pa tients with congenital enteropeptidase deficiency who were from two familie s. We found compound heterozygosity for nonsense mutations (S712X/R857X) in two affected siblings and found compound heterozygosity for a nonsense mut ation (Q261X) and a frameshift mutation (FsQ902) in the third patient. In a ccordance with the biochemical findings, all four defective alleles identif ied are predicted null alleles leading to a gene product not containing the active site of the enzyme. These data provide first evidence that proenter opeptidase-gene mutations are the primary cause of congenital enteropeptida se deficiency.