Congenital secretory diarrhoea caused by activating germline mutations in GUCY2C

Thomas Müller, Insha Rasool, Peter Heinz-Erian, Eva Mildenberger, Christian Hülstrunk, Andreas Müller, Laurent Michaud, Bart G.P. Koot, Antje Ballauff, Julia Vodopiutz, Stefan Rosipal, Britt Sabina Petersen, Andre Franke, Irene Fuchs, Heiko Witt, Heinz Zoller, Andreas R. Janecke, Sandhya S. Visweswariah

Research output: Contribution to journalArticlepeer-review

70 Scopus citations


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 4â €..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.

Original languageEnglish
Pages (from-to)1306-1313
Number of pages8
Issue number8
StatePublished - 1 Aug 2016
Externally publishedYes


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