title: Reduced sodium/proton exchanger NHE3 activity causes congenital sodium diarrhea.
abstract: Congenital sodium diarrhea (CSD) refers to an intractable diarrhea of intrauterine onset with high fecal sodium loss. CSD is clinically and genetically heterogeneous. Syndromic CSD is caused by SPINT2 mutations. While we recently described four cases of the non-syndromic form of CSD that were caused by dominant activating mutations in intestinal receptor guanylate cyclase C (GC-C), the genetic cause for the majority of CSD is still unknown. Therefore, we aimed to determine the genetic cause for non-GC-C non-syndromic CSD in 18 patients from 16 unrelated families applying whole-exome sequencing and/or chromosomal microarray analyses and/or direct Sanger sequencing. SLC9A3 missense, splicing and truncation mutations, including an instance of uniparental disomy, and whole-gene deletion were identified in nine patients from eight families with CSD. Two of these nine patients developed inflammatory bowel disease (IBD) at 4 and 16 years of age. SLC9A3 encodes Na(+)/H(+) antiporter 3 (NHE3), which is the major intestinal brush-border Na(+)/H(+) exchanger. All mutations were in the NHE3 N-terminal transport domain, and all missense mutations were in the putative membrane-spanning domains. Identified SLC9A3 missense mutations were functionally characterized in plasma membrane NHE null fibroblasts. SLC9A3 missense mutations compromised NHE3 activity by reducing basal surface expression and/or loss of basal transport function of NHE3 molecules, whereas acute regulation was normal. This study identifies recessive mutations in NHE3, a downstream target of GC-C, as a cause of CSD and implies primary basal NHE3 malfunction as a predisposition for IBD in a subset of patients.
authors.affiliation: Department of Pediatrics I, Division of Human Genetics.
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Janecke
authors.affiliation: Department of Pediatrics I.
authors.forename: Peter
authors.initials: P
authors.lastname: Heinz-Erian
authors.affiliation: Department of Medicine, Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Jianyi
authors.initials: J
authors.lastname: Yin
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel 24105, Germany.
authors.forename: Britt-Sabina
authors.initials: BS
authors.lastname: Petersen
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel 24105, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: Division of Human Genetics.
authors.forename: Silvia
authors.initials: S
authors.lastname: Lechner
authors.affiliation: Department of Pediatrics I.
authors.forename: Irene
authors.initials: I
authors.lastname: Fuchs
authors.affiliation: Department of Medical Genetics, McGill University Health Centre, Montreal, Canada H3H 1P3.
authors.forename: Serge
authors.initials: S
authors.lastname: Melancon
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Medicine, and Children's Hospital, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Holm H
authors.initials: HH
authors.lastname: Uhlig
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Medicine, and Children's Hospital, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Travis
authors.affiliation: Service des maladies digestives et respiratoires de l'enfant, Centre de référence des maladies digestives rares, Hôpital R Debré, Paris 75935, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Marinier
authors.affiliation: Department of Hepatology and GI Endoscopy, University Children's Hospital, Belgrade 11000, Serbia.
authors.forename: Vojislav
authors.initials: V
authors.lastname: Perisic
authors.affiliation: Department of Hepatology and GI Endoscopy, University Children's Hospital, Belgrade 11000, Serbia.
authors.forename: Nina
authors.initials: N
authors.lastname: Ristic
authors.affiliation: Zentrum für Kinder-und Jugendmedizin, Universitätsklinikum, Freiburg 79106, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Gerner
authors.affiliation: Paediatrics and Child Health, University of Birmingham, Birmingham B4 6NH, UK.
authors.forename: Ian W
authors.initials: IW
authors.lastname: Booth
authors.affiliation: Department of Medical Genetics, University of Helsinki, Helsinki 00014, Finland.
authors.forename: Satu
authors.initials: S
authors.lastname: Wedenoja
authors.affiliation: Department of Internal Medicine, Medical University of Innsbruck, Innsbruck 6020, Austria.
authors.forename: Nadja
authors.initials: N
authors.lastname: Baumgartner
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Wien 1090, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Vodopiutz
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Sherbrooke University, Sherbrooke, Canada J1H 5N4.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Frechette-Duval
authors.affiliation: Abteilung Allgemeine Pädiatrie & Neonatologie, Zentrum für Kinderheilkunde und Jugendmedizin, Justus-Liebig-Universität, Gießen 35392, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: De Lafollie
authors.affiliation: Stollery Children's Hospital, University of Alberta, Edmonton, Canada T6G 2B7.
authors.forename: Rabindranath
authors.initials: R
authors.lastname: Persad
authors.affiliation: SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8.
authors.forename: Neil
authors.initials: N
authors.lastname: Warner
authors.affiliation: Department of Medicine, Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: C Ming
authors.initials: CM
authors.lastname: Tse
authors.affiliation: Department of Medicine, Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Karan
authors.initials: K
authors.lastname: Sud
authors.affiliation: Department of Medicine, Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Zachos
authors.affiliation: Department of Medicine, Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Rafiquel
authors.initials: R
authors.lastname: Sarker
authors.affiliation: Department of Medicine, Albany Medical Center, Albany, NY 12208, USA.
authors.forename: Xinjun
authors.initials: X
authors.lastname: Zhu
authors.affiliation: SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8, Department of Biochemistry, Department of IMS, Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of Toronto, Toronto, ON, Canada M5G 1X8 and.
authors.forename: Aleixo M
authors.initials: AM
authors.lastname: Muise
authors.affiliation: Abteilung Allgemeine Pädiatrie & Neonatologie, Zentrum für Kinderheilkunde und Jugendmedizin, Justus-Liebig-Universität, Gießen 35392, Germany.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Zimmer
authors.affiliation: Pädiatrische Ernährungsmedizin, Else Kröner-Fresenius-Zentrum für Ernährungsmedizin, Technische Universität München, Freising-Weihenstephan 85350, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Witt
authors.affiliation: Department of Internal Medicine, Medical University of Innsbruck, Innsbruck 6020, Austria.
authors.forename: Heinz
authors.initials: H
authors.lastname: Zoller
authors.affiliation: Department of Medicine, Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Donowitz
authors.affiliation: Department of Pediatrics I, thomas.mueller@tirol-kliniken.at.
authors.forename: Thomas
authors.initials: T
authors.lastname: Müller
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D003967:Diarrhea / Q000151:congenital* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000503:physiopathology; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008871:Microvilli / Q000378:metabolism; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics*; D055815:Young Adult
chemical_list: C000613385:SLC9A3 protein, human; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers