Mutations in the Proenteropeptidase Gene Are the Molecular Cause of Congenital Enteropeptidase Deficiency

Abstract

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

Discovery and characterization of a small‐molecule enteropeptidase inhibitor, SCO‐792

“…The activated trypsin in turn activates downstream digestive enzymes, such as chymotrypsinogen, proesterase, procarboxypeptidases A and B, and prolipase, which allow the absorption of amino acids and triglycerides in the gut . Congenital enteropeptidase deficiency in humans has resulted in intestinal malabsorption and a lean phenotype, which suggest the pivotal role of this enzyme in regulating body homeostasis . Interestingly, a recent seminal study suggested that inhibiting gut enteropeptidase may be a novel strategy for correcting obesity .…”

Recent Progress in Congenital Diarrheal Disorders

“…Only 13 cases of primary enterokinase deficiency have been reported. Three additional patients were reported with a similar clinical picture, but with unmeasured intestinal enterokinase activity [23]. All mutations identified in the proenteropeptidase gene are null mutations that predict the absence of a correctly formed active site.…”

“…Proteinase-activated receptor 2 is present at the apical and basolateral membrane of enterocytes; activation of this receptor by trypsin stimulates enterocytes to secrete eicosanoids, which act locally in the intestinal wall to regulate epithelial growth [23]. Therefore, in addition to its purely digestive role, enterokinase localization on the luminal surface of the duodenal villi possibly contributes to enterocyte growth by generating active trypsin on the cell surface.…”

“…Therefore, in addition to its purely digestive role, enterokinase localization on the luminal surface of the duodenal villi possibly contributes to enterocyte growth by generating active trypsin on the cell surface. The human genetic locus appears to be close to the gene for β-amyloid precursor protein at band 21q.21.2 [23]. The human proenteropeptidase gene consists of 25 exons (24 introns) and it spans 88 kb.…”

The genetic and molecular bases of monogenic disorders affecting proteolytic systems

“…3 4 Loss of function mutations in enterokinase cause congenital enteropeptidase deficiency with retardation of growth during childhood, chronic diarrhoea, and generalised oedema. 5 This severe protein malabsorption is prominent during childhood and corresponds to a lack of enterokinase dependent activation of digestive enzymes.…”