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Congenital secretory diarrhoea caused by activating germline mutations in GUCY2C

Mueller, Thomas and Rasool, Insha and Heinz-Erian, Peter and Mildenberger, Eva and Huelstrunk, Christian and Mueller, Andreas and Michaud, Laurent and Koot, Bart GP and Ballauff, Antje and Vodopiutz, Julia and Rosipal, Stefan and Petersen, Britt-Sabina and Franke, Andre and Fuchs, Irene and Witt, Heiko and Zoller, Heinz and Janecke, Andreas R and Visweswariah, Sandhya S (2016) Congenital secretory diarrhoea caused by activating germline mutations in GUCY2C. In: GUT, 65 (8). pp. 1306-1313.

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Official URL: http://dx.doi.org/10.1136/gutjnl-2015-309441


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.

Item Type: Journal Article
Publication: GUT
Additional Information: Copy right for this article belongs to the BMJ PUBLISHING GROUP, BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND
Department/Centre: Division of Biological Sciences > Molecular Reproduction, Development & Genetics
Date Deposited: 24 Aug 2016 09:22
Last Modified: 24 Aug 2016 09:22
URI: http://eprints.iisc.ac.in/id/eprint/54511

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