Paediatrics Publications

Title

Mutations in SPINT2 Cause a Syndromic Form of Congenital Sodium Diarrhea

Authors

Peter Heinz-Erian, Innsbruck Medical University, Innsbruck, Austria
Thomas Müller, Innsbruck Medical University, Innsbruck, Austria
Birgit Krabichler, Innsbruck Medical University, Innsbruck, Austria
Melanie Schranz, Innsbruck Medical University, Innsbruck, Austria
Christian Becker, University of Cologne, Cologne, Germany
Franz Rüschendorf, Max Delbrück Centre, Berlin, Germany
Peter Nürnberg, University of Cologne, Cologne, Germany
Bernard Rossier, University of Lausanne, Lausanne, Switzerland
Mihailo Vujic, University of Gothenburg, Gothenburg, Sweden
Ian W. Booth, University of Birmingham
Christer Holmberg, University of Helsinki, Helsinki, Finland
Cisca Wijmenga, University of Groningen, The Netherlands
Giedre Grigelioniene, Karolinska University Hospital, Stockholm, Sweden
C. M. Frank Kneepkens, University of Amsterdam, Amsterdam, The Netherlands
Stefan Rosipal, Pediatric Centre of Preventive Cardiovascular Medicine, Poprad-Velka, Slovakia
Martin Mistrik, General Hospital, Spisska Nova Ves, Slovakia
Matthias Kappler, Ludwig-Maximilians University, Munich, Germany
Laurent Michaud, University of Lille, Lille, France
Ludwig-Christoph Dóczy, Innsbruck Medical University, Innsbruck, Austria
Victoria Mok Siu, University of Western Ontario
Marie Krantz, University of Gothenburg, Gothenburg, Sweden
Heinz Zoller, Innsbruck Medical University, Innsbruck, Austria
Gerd Utermann, Innsbruck Medical University, Innsbruck, Austria
Andreas R. Janecke, Innsbruck Medical University, Innsbruck, Austria

Document Type

Article

Publication Date

1-29-2009

Journal

American Journal of Human Genetics

Volume

84

Issue

2

First Page

188

Last Page

196

URL with Digital Object Identifier

10.1016/j.ajhg.2009.01.004

Abstract

Autosomal-recessive congenital sodium diarrhea (CSD) is characterized by perinatal onset of a persistent watery diarrhea with nonproportionally high fecal sodium excretion. Defective jejunal brush-border Na(+)/H(+) exchange has been reported in three sporadic patients, but the molecular basis of the disease has not been elucidated. We reviewed data from a large cohort of CSD patients (n = 24) and distinguished CSD associated with choanal or anal atresia, hypertelorism, and corneal erosions--i.e., a syndromic form of CSD--occurring in ten families from an isolated form--i.e., classic CSD--presenting in seven families. Patients from both groups have a high risk of mortality due to immediate electrolyte imbalances and complications from long-term parenteral nutrition in the first years of life, but survivors can eventually adapt to partial or complete enteral nutrition. A genome-wide SNP scan was applied and identified a homozygous c.593-1G-->A splicing mutation in SPINT2, encoding a Kunitz-type serine-protease inhibitor, in one extended kindred with syndromic CSD. The same mutation and four distinct, homozygous or compound heterozygous mutations (p.Y163C, c.1A-->T, c.337+2T-->C, c.553+2T-->A) were identified in all syndromic patients. No SPINT2 mutations were found in classic-CSD patients. SPINT2 mutations were associated with loss of protein synthesis or failure to inhibit the serine protease trypsin in vitro. We delineate syndromic CSD as a distinct disease entity caused by SPINT2 loss-of-function mutations. SPINT2 mutations might lead to an excess of yet unknown serine protease activity in affected tissues.