title: Congenital secretory diarrhoea caused by activating germline mutations in GUCY2C.
abstract: 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.
authors.affiliation: Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Müller
authors.affiliation: Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India.
authors.forename: Insha
authors.initials: I
authors.lastname: Rasool
authors.affiliation: Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Heinz-Erian
authors.affiliation: Department of Neonatology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Mildenberger
authors.affiliation: Department of Neonatology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hülstrunk
authors.affiliation: Abt.Neonatologie (NIPS) Perinatalzentrum, Bonn, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Müller
authors.affiliation: Clinique de Pédiatrie, Pôle enfant, Hôpital J de Flandre CHRU de Lille, Inserm U995, Faculté de Médecine, Université de Lille 2, Lille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Michaud
authors.affiliation: Department of Pediatrics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Bart G P
authors.initials: BG
authors.lastname: Koot
authors.affiliation: Kinderklinik, Helios-Klinikum Krefeld, Krefeld, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Ballauff
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Vodopiutz
authors.affiliation: Pediatric Clinic of Preventive Medicine in Poprad, Slovak Health University, Poprad, Slovakia.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rosipal
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Kiel, Germany.
authors.forename: Britt-Sabina
authors.initials: BS
authors.lastname: Petersen
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Irene
authors.initials: I
authors.lastname: Fuchs
authors.affiliation: Pädiatrische Ernährungsmedizin, Else Kröner-Fresenius-Zentrum (EKFZ) für Ernährungsmedizin, Technische Universität München (TUM), Freising-Weihenstephan, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Witt
authors.affiliation: Department of Internal Medicine, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Heinz
authors.initials: H
authors.lastname: Zoller
authors.affiliation: Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Janecke
authors.affiliation: Department of Neonatology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Sandhya S
authors.initials: SS
authors.lastname: Visweswariah
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000503:physiopathology; D003967:Diarrhea / Q000151:congenital* / Q000235:genetics / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease; D006157:Guanosine Monophosphate / Q000378:metabolism; D006801:Humans; D007223:Infant; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000503:physiopathology; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics / Q000503:physiopathology; D020125:Mutation, Missense; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled / Q000235:genetics*; D018000:Receptors, Peptide / Q000235:genetics*; D012964:Sodium / Q000378:metabolism
chemical_list: D018000:Receptors, Peptide; D006157:Guanosine Monophosphate; D012964:Sodium; C000613654:GUCY2C protein, human; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled
keywords: BACTERIAL ENTEROTOXINS; CHRONIC DIARRHOEA; GUANYLATE CYCLASE; INTESTINAL ION TRANSPORT; PAEDIATRIC DIARRHOEA