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Mutations in SPINT2 Cause a Syndromic Form of Congenital Sodium Diarrhea

By Peter Heinz-Erian, Thomas Müller, Birgit Krabichler, Melanie Schranz, Christian Becker, Franz Rüschendorf, Peter Nürnberg, Bernard Rossier, Mihailo Vujic, Ian W. Booth, Christer Holmberg, Cisca Wijmenga, Giedre Grigelioniene, C. M. Frank Kneepkens, Stefan Rosipal, Martin Mistrik, Matthias Kappler, Laurent Michaud, Ludwig-Christoph Dóczy, Victoria Mok Siu, Marie Krantz, Heinz Zoller, Gerd Utermann and Andreas R. Janecke


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

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Publisher: Elsevier
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Provided by: PubMed Central
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