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

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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. 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. 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. 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
Issue number8
Publication statusPublished - 2016

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