Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 70 (1), 20-5

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


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

Andreas Holzinger et al. Am J Hum Genet.


Enteropeptidase (enterokinase [E.C.]) 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.


Figure  1
Figure 1
Mutations in the proenteropeptidase gene. A, Analysis of index patient in family 1. Nonsense mutations were identified in exons 18 and 22. B, Analysis of index patient in family 2, which led to identification of a nonsense mutation in exon 8 and of a frameshift mutation in exon 23.
Figure  2
Figure 2
Segregation analysis of families with congenital enteropeptidase deficiency. The sequence alterations of the pathogenic mutation are underlined; the three-digit numerals 241, 237, 231, 229, and 235 denote the fragment lengths of the intron 6 polymorphic CA repeat. In both families, defective alleles are inherited from heterozygous parents. Note that the 1472C→T (A491V) mutation (or rare polymorphism) in family 2 is part of an allele also affected by a nonsense mutation. Position 1473 is dimorphic (G/A) and informative in family 2 (i.e., the 781C→T mutation segregates with the T allele) but not in family 1.
Figure  3
Figure 3
Position of mutations (red arrows), in relation to proenteropeptidase exon organization, domains, and amino acid residues forming the active site of the serine protease domain (H825, D876, and S971 [blue arrows]). All four mutations identified are null mutations predicting the absence of a correctly formed active site. The previously described modular structure of proenteropeptidase domains, based on primary-structure comparison, correlates with exon boundaries. SA = signal/anchor sequence; LDLR = LDL receptor–like domain; Muc = mucin-domain; Meprin = meprin-like domain; C1r/s = complement component C1r-like domain; MSCR = macrophage scavenger receptor–like domain.

Similar articles

See all similar articles

Cited by 11 PubMed Central articles

See all "Cited by" articles

MeSH terms