ArticleHuman molecular genetics2015
Reduced sodium/proton exchanger NHE3 activity causes congenital sodium diarrhea.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 80 papers.
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Who cites it
80 citing papers in PubMed, 132 citations in OpenAlex.
- A biochemical difference between HAI-2 variants causing syndromic and non-syndromic Congenital Sodium Diarrhea.PloS one · 2026Article
- Differential regulation of NHE3 expression in type 1 and type 2 diabetic intestine: impaired endosomal regulation of NHE3 expression in type 1 diabetes.American journal of physiology. Cell physiology · 2025Article
- The SLC-ome of membrane transport: From molecular discovery to physiology and clinical applications.Physiological reviews · 2025Review
- Differential Regulation of NHE3 Expression in Type 1 and Type 2 Diabetic Intestine: Impaired Endosomal Regulation of NHE3 Expression in Type 1 Diabetes.bioRxiv : the preprint server for biology · 2025Article
- Monogenic inflammatory bowel disease: An unfolding enigma.World journal of clinical pediatrics · 2025Review
- Non-Syndromic Congenital Sodium Diarrhoea With a SLC9A3 Gene Variant: A Case Report.Journal of paediatrics and child health · 2025Article
- Advances in Understanding Intestinal Homeostasis: Lessons from Inflammatory Bowel Disease and Monogenic Intestinal Disorder Pathogenesis.International journal of molecular sciences · 2025Review
- Article
- Congenital enteropathy caused by ezrin deficiency.Human genetics · 2025Article
- The Genetic Architecture of Congenital Diarrhea and Enteropathy.The New England journal of medicine · 2025Article
- Short-chain fatty acids: linking diet, the microbiome and immunity.Nature reviews. Immunology · 2024Review
- Breaking Down Barriers: Epithelial Contributors to Monogenic IBD Pathogenesis.Inflammatory bowel diseases · 2024Review
- Diet management in congenital diarrheas and enteropathies - general concepts and disease-specific approach, a narrative review.The American journal of clinical nutrition · 2024Review
- T-bet Regulates Ion Channels and Transporters and Induces Apoptosis in Intestinal Epithelial Cells.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Modeling the cell biology of monogenetic intestinal epithelial disorders.The Journal of cell biology · 2024Review
- The macrocycle inhibitor landscape of SLC-transporter.Molecular informatics · 2024Article
- SPINT2 mutations in the Kunitz domain 2 found in SCSD patients inactivate HAI-2 as prostasin inhibitor via abnormal protein folding and N-glycosylation.Human molecular genetics · 2024Article
- New functions and roles of the NaPflugers Archiv : European journal of physiology · 2024Review
- Regulation of the intestinal NaAmerican journal of physiology. Cell physiology · 2024Article
- Precision medicine in monogenic inflammatory bowel disease: proposed mIBD REPORT standards.Nature reviews. Gastroenterology & hepatology · 2023Review
20 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
33 authors at 20 institutions in 8 countries.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.