SPINT2 (HAI-2) missense variants identified in congenital sodium diarrhea/tufting enteropathy affect the ability of HAI-2 to inhibit prostasin but not matriptase

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

DOI

  • Lasse Holt-Danborg, Univ Copenhagen, University of Copenhagen, Panum Inst, Dept Cellular & Mol Med
  • ,
  • Julia Vodopiutz, Med Univ Vienna, Medical University of Vienna, Dept Pediat & Adolescent Med
  • ,
  • Annika W. Nonboe, Univ Copenhagen, University of Copenhagen, Panum Inst, Dept Cellular & Mol Med
  • ,
  • Jan De Laffolie, Justus Liebig Univ, Justus Liebig University Giessen, Abt Allgemeine Padiat & Neonatol, Zentrum Kinderheilkunde & Jugendmed
  • ,
  • Signe Skovbjerg, Univ Copenhagen, University of Copenhagen, Panum Inst, Dept Cellular & Mol Med
  • ,
  • Victorien M. Wolters, UMC Utrecht, Utrecht University, Utrecht University Medical Center, Wilhelmina Kinderziekenhuis, Dept Pediat Gastroenterol, WKZ
  • ,
  • Thomas Mueller, Med Univ Innsbruck, Medical University of Innsbruck, Dept Pediat 1
  • ,
  • Benjamin Hetzer, Med Univ Innsbruck, Medical University of Innsbruck, Dept Pediat 1
  • ,
  • Alexander Querfurt, Gesundheit Nord gGmbH, Klinikum Bremen-Mitte, Klin Verbund Bremen, Klin Kinder & Jugendmed, Klinikum Bremen Mitte,Prof Hess Kinderklin
  • ,
  • Klaus-Peter Zimmer, Justus Liebig Univ, Justus Liebig University Giessen, Abt Allgemeine Padiat & Neonatol, Zentrum Kinderheilkunde & Jugendmed
  • ,
  • Jan K. Jensen
  • Andreas Entenmann, Med Univ Innsbruck, Medical University of Innsbruck, Dept Pediat 1
  • ,
  • Peter Heinz-Erian, Med Univ Innsbruck, Medical University of Innsbruck, Dept Pediat 1
  • ,
  • Lotte K. Vogel, Univ Copenhagen, University of Copenhagen, Panum Inst, Dept Cellular & Mol Med
  • ,
  • Andreas R. Janecke, Med Univ Innsbruck, Medical University of Innsbruck, Div Human Genet

The syndromic form of congenital sodium diarrhea (SCSD) is caused by bi-allelic mutations in SPINT2, which encodes a Kunitz-type serine protease inhibitor (HAI-2). We report three novel SCSD patients, two novel SPINT2 mutations and review published cases. The most common findings in SCSD patients were choanal atresia (20/34) and keratitis of infantile onset (26/34). Characteristic epithelial tufts on intestinal histology were reported in 13/34 patients. Of 13 different SPINT2 variants identified in SCSD, 4 are missense variants and localize to the second Kunitz domain (KD2) of HAI-2. HAI-2 has been implicated in the regulation of the activities of several serine proteases including prostasin and matriptase, which are both important for epithelial barrier formation. No patient with bi-allelic stop mutations was identified, suggesting that at least one SPINT2 allele encoding a protein with residual HAI-2 function is necessary for survival. We show that the SCSD-associated HAI-2 variants p. Phe161Val, p. Tyr163Cys and p. Gly168Ser all display decreased ability to inhibit prostasin-catalyzed cleavage. However, the SCSD-associated HAI-2 variants inhibited matriptase as efficiently as the wild-type HAI-2. Homology modeling indicated limited solvent exposure of the mutated amino acids, suggesting that they induce misfolding of KD2. This suggests that prostasin needs to engage with an exosite motif located on KD2 in addition to the binding loop (Cys47/Arg48) located on the first Kunitz domain in order to inhibit prostasin. In conclusion our data suggests that SCSD is caused by lack of inhibition of prostasin or a similar protease in the secretory pathway or on the plasma membrane.

Original languageEnglish
JournalHuman Molecular Genetics
Volume28
Issue5
Pages (from-to)828-841
Number of pages14
ISSN0964-6906
DOIs
Publication statusPublished - 1 Mar 2019

    Research areas

  • FACTOR ACTIVATOR INHIBITOR-2, PROTEASE MATRIPTASE, TUFTING ENTEROPATHY, EPCAM, CLEAVAGE, ZYMOGEN, CLOSURE, GENE

See relations at Aarhus University Citationformats

ID: 171587793