PT  - JOURNAL ARTICLE
AU  - Thomas Müller
AU  - Insha Rasool
AU  - Peter Heinz-Erian
AU  - Eva Mildenberger
AU  - Christian Hülstrunk
AU  - Andreas Müller
AU  - Laurent Michaud
AU  - Bart G P Koot
AU  - Antje Ballauff
AU  - Julia Vodopiutz
AU  - Stefan Rosipal
AU  - Britt-Sabina Petersen
AU  - Andre Franke
AU  - Irene Fuchs
AU  - Heiko Witt
AU  - Heinz Zoller
AU  - Andreas R Janecke
AU  - Sandhya S Visweswariah
TI  - Congenital secretory diarrhoea caused by activating germline mutations in <em>GUCY2C</em>
AID  - 10.1136/gutjnl-2015-309441
DP  - 2016 Aug 01
TA  - Gut
PG  - 1306--1313
VI  - 65
IP  - 8
4099  - http://gut.bmj.com/content/65/8/1306.short
4100  - http://gut.bmj.com/content/65/8/1306.full
SO  - Gut2016 Aug 01; 65
AB  - 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.