Reduced sodium-proton exchanger NHE3 activity causes congenital sodium diarrhea.

Andreas R Janecke, Peter Heinz-Erian, Jianyi Yin, Britt-Sabina Petersen, Andre Franke, Silvia Lechner, Irene Fuchs, Serge Melancon, Holm H Uhlig, Simon Travis, Evelyne Marinier, Vojislav Perisic, Nina Ristic, Patrick Gerner, Ian W Booth, Satu Wedenoja, Nadja Baumgartner, Julia Vodopiutz, Marie-Christine Frechette-Duval, Jan De Lafollie, Rabindranath Persad, Neil Warner, C Ming Tse, Karan Sud, Nicholas C Zachos, Rafiquel Sarker, Xinjun Zhu, Aleixo M Muise, Klaus-Peter Zimmer, Heiko Witt, Heinz Zoller, Mark Donowitz, Thomas Müller
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Human molecular genetics
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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 9 patients from 8 families with CSD. Two of these 9 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, while 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.