Reduced sodium/proton exchanger NHE3 activity causes congenital sodium diarrhea

Hum Mol Genet. 2015 Dec 1;24(23):6614-23. doi: 10.1093/hmg/ddv367.

Andreas R Janecke ¹, Peter Heinz-Erian ², Jianyi Yin ³, Britt-Sabina Petersen ⁴, Andre Franke ⁴, Silvia Lechner ⁵, Irene Fuchs ², Serge Melancon ⁶, Holm H Uhlig ⁷, Simon Travis ⁷, Evelyne Marinier ⁸, Vojislav Perisic ⁹, Nina Ristic ⁹, Patrick Gerner ¹⁰, Ian W Booth ¹¹, Satu Wedenoja ¹², Nadja Baumgartner ¹³, Julia Vodopiutz ¹⁴, Marie-Christine Frechette-Duval ¹⁵, Jan De Lafollie ¹⁶, Rabindranath Persad ¹⁷, Neil Warner ¹⁸, C Ming Tse ³, Karan Sud ³, Nicholas C Zachos ³, Rafiquel Sarker ³, Xinjun Zhu ¹⁹, Aleixo M Muise ²⁰, Klaus-Peter Zimmer ¹⁶, Heiko Witt ²¹, Heinz Zoller ¹³, Mark Donowitz ³, Thomas Müller ²²

Affiliations

1 Department of Pediatrics I, Division of Human Genetics.
2 Department of Pediatrics I.
3 Department of Medicine, Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
4 Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel 24105, Germany.
5 Division of Human Genetics.
6 Department of Medical Genetics, McGill University Health Centre, Montreal, Canada H3H 1P3.
7 Translational Gastroenterology Unit, Nuffield Department of Medicine, and Children's Hospital, University of Oxford, Oxford OX3 9DU, UK.
8 Service des maladies digestives et respiratoires de l'enfant, Centre de référence des maladies digestives rares, Hôpital R Debré, Paris 75935, France.
9 Department of Hepatology and GI Endoscopy, University Children's Hospital, Belgrade 11000, Serbia.
10 Zentrum für Kinder-und Jugendmedizin, Universitätsklinikum, Freiburg 79106, Germany.
11 Paediatrics and Child Health, University of Birmingham, Birmingham B4 6NH, UK.
12 Department of Medical Genetics, University of Helsinki, Helsinki 00014, Finland.
13 Department of Internal Medicine, Medical University of Innsbruck, Innsbruck 6020, Austria.
14 Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Wien 1090, Austria.
15 Department of Pediatrics, Faculty of Medicine, Sherbrooke University, Sherbrooke, Canada J1H 5N4.
16 Abteilung Allgemeine Pädiatrie & Neonatologie, Zentrum für Kinderheilkunde und Jugendmedizin, Justus-Liebig-Universität, Gießen 35392, Germany.
17 Stollery Children's Hospital, University of Alberta, Edmonton, Canada T6G 2B7.
18 SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8.
19 Department of Medicine, Albany Medical Center, Albany, NY 12208, USA.
20 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.
21 Pädiatrische Ernährungsmedizin, Else Kröner-Fresenius-Zentrum für Ernährungsmedizin, Technische Universität München, Freising-Weihenstephan 85350, Germany.
22 Department of Pediatrics I, [email protected].

PMID: 26358773 DOI: 10.1093/hmg/ddv367

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.

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