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Congenital secretory diarrhoea caused by activating germline mutations in GUCY2C
  1. Thomas Müller1,
  2. Insha Rasool2,
  3. Peter Heinz-Erian1,
  4. Eva Mildenberger3,
  5. Christian Hülstrunk3,
  6. Andreas Müller4,
  7. Laurent Michaud5,
  8. Bart G P Koot6,
  9. Antje Ballauff7,
  10. Julia Vodopiutz8,
  11. Stefan Rosipal9,
  12. Britt-Sabina Petersen10,
  13. Andre Franke10,
  14. Irene Fuchs1,
  15. Heiko Witt11,
  16. Heinz Zoller12,
  17. Andreas R Janecke1,
  18. Sandhya S Visweswariah3
  1. 1Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria
  2. 2Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India
  3. 3Department of Neonatology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
  4. 4Abt.Neonatologie (NIPS) Perinatalzentrum, Bonn, Germany
  5. 5Clinique de Pédiatrie, Pôle enfant, Hôpital J de Flandre CHRU de Lille, Inserm U995, Faculté de Médecine, Université de Lille 2, Lille, France
  6. 6Department of Pediatrics, Academic Medical Center, Amsterdam, The Netherlands
  7. 7Kinderklinik, Helios-Klinikum Krefeld, Krefeld, Germany
  8. 8Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
  9. 9Pediatric Clinic of Preventive Medicine in Poprad, Slovak Health University, Poprad, Slovakia
  10. 10Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Kiel, Germany
  11. 11Pädiatrische Ernährungsmedizin, Else Kröner-Fresenius-Zentrum (EKFZ) für Ernährungsmedizin, Technische Universität München (TUM), Freising-Weihenstephan, Germany
  12. 12Department of Internal Medicine, Medical University of Innsbruck, Innsbruck, Austria
  1. Correspondence to Ass-Prof Dr Andreas Janecke, Department of Pedatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria; andreas.janecke{at} Prof Sandhya S Visweswariah, Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Biological Sciences Building, GA09, Bangalore 560012, Karnataka, India; sandhya{at}


Objective Congenital sodium diarrhoea (CSD) refers to a form of secretory diarrhoea with intrauterine onset and high faecal losses of sodium without congenital malformations. The molecular basis for CSD remains unknown. We clinically characterised a cohort of infants with CSD and set out to identify disease-causing mutations by genome-wide genetic testing.

Design We performed whole-exome sequencing and chromosomal microarray analyses in 4 unrelated patients, followed by confirmatory Sanger sequencing of the likely disease-causing mutations in patients and in their family members, followed by functional studies.

Results We identified novel de novo missense mutations in GUCY2C, the gene encoding receptor guanylate cyclase C (GC-C) in 4 patients with CSD. One patient developed severe, early-onset IBD and chronic arthritis at 4 years of age. GC-C is an intestinal brush border membrane-bound guanylate cyclase, which functions as receptor for guanylin, uroguanylin and Escherichia coli heat-stable enterotoxin. Mutations in GUCY2C were present in different intracellular domains of GC-C, and were activating mutations that enhanced intracellular cyclic guanosine monophosphate accumulation in a ligand-independent and ligand-stimulated manner, following heterologous expression in HEK293T cells.

Conclusions Dominant gain-of-function GUCY2C mutations lead to elevated intracellular cyclic guanosine monophosphate levels and could explain the chronic diarrhoea as a result of decreased intestinal sodium and water absorption and increased chloride secretion. Thus, mutations in GUCY2C indicate a role for this receptor in the pathogenesis of sporadic CSD.


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