This website provides information on patients with mutations in the gene SLC9A3 (solute‐carrier family 9, member A3; also known as NHE3), including clinical data, molecular data, management, and research options.

SLC9A3 is located at chromosome 5p15.33 and encodes the sodium (Na⁺)/proton (H⁺) exchanger 3 isoform (NHE3)—a brush‐border (apical membrane) epithelial transporter expressed predominantly in the gastrointestinal tract and renal proximal tubules where it regulates sodium and indirectly bicarbonate (HCO3-) and water (re)absorption which helps to control the body’s fluid levels (and consequently blood pressure) and acid–base (pH) homeostasis. It is also expressed in other epithelia, such as the male epididymis, vas deferens and testes where it plays important roles in seminal fluid levels and acidification essential for male reproductive health.

Loss‐of‐function mutations in SLC9A3 are a known cause of autosomal-recessive congenital secretory sodium diarrhea (CSD) (often referenced as “DIAR8” in the Online Mendelian Inheritance in Man (OMIM) database; also referenced as ORPHA:103908 in Orphanet). This is a rare genetic, non-syndromic ion transport defect characterized by congenital onset of severe watery diarrhea containing high concentrations of sodium and systemic hyponatremia and metabolic acidosis. Other reported features include the later development of ileal/colonic ulceration and inflammatory‐bowel‐disease (IBD)-like features during childhood and adolescence.

In addition, some patients harboring SLC9A3 deletions/variants are present in males with cystic fibrosis who also exhibit congenital bilateral absence of the vas deferens (CBAVD). SLC9A3 variants likely act as a modifier gene (rather than as a sole causative gene) together with variants of the cystic fibrosis gene CFTR, leading to disrupted male reproductive tract development and function; i.e., impaired seminal fluid levels and acidification, obstructive azoospermia and testicular atrophy, resulting in male sterility.

Not all individuals with a genetic variation or mutation in the SLC9A3 gene have all these features.

This website was created to share and collect information about clinic, management, and research projects to gather more knowledge and provide better treatment of patients with mutations in the SLC9A3 gene.

John Orlowski, PhD, Department of Physiology, McGill University, Montreal, Quebec, Canada, john.orlowski@mcgill.ca