Rare mutation in the SLC26A3 transporter causes life-long diarrhoea with metabolic alkalosis

Abstract

SLC26A3, a chloride/bicarbonate transporter mainly expressed in the intestines, plays a pivotal role in chloride absorption. We present a 23-year-old woman with a history of congenital chloride diarrhoea (CCD) and renal transplant who was admitted for rehydration and treatment of acute kidney injury after she presented with an acute diarrhoeal episode. Laboratory investigations confirmed metabolic alkalosis and severe hypochloraemia, consistent with her underlying CCD. This contrasts with most other forms of diarrhoea, which are normally associated with metabolic acidosis. Genetic testing was offered and revealed a homozygous non-sense mutation in SLC26A3 (Gly-187-Stop). This loss-of-function mutation results in bicarbonate retention in the blood and chloride loss into the intestinal lumen. Symptomatic management with daily NaCl and KCl oral syrups was supplemented with omeprazole therapy. The loss of her own kidneys is most likely due to crystal-induced nephropathy secondary to chronic volume contraction and chloride depletion. This case summarises the pathophysiology and management of CCD.

Figure 1

Congenital chloride diarrhoea pedigree. Individuals III.e and III.f are first-degree cousins, and are the parents of the patient (IV.d). Individual IV.f is her 17-year-old brother. He is the only additional family member diagnosed with congenital chloride diarrhoea, albeit a milder form than his sister (IV.d) and without renal complications. There are no other family members with congenital chloride diarrhoea and no other diseases that run in the family.

Figure 2

Congenital chloride diarrhoea (CCD) variant of the SLC26A3. SLC26A3 is a 37.8 kb gene composed of 21 exons located on the long arm of chromosome 7. The gene encodes a 764 amino acid transmembrane protein. After translation, the mature protein is trafficked to the apical surface of the epithelial cell. It has 12 transmembrane domains, and a permease domain thus functioning as an ion transporter. There are over 55 mutations in the SLC26A3 gene reported worldwide that cause congenital chloride diarrhoea (autosomal recessive). One of them is in exon 5, resulting in Gly187Stop that accounts for more than 90% of CCD cases in the Arab population. This non-sense mutation truncates the protein at the level of transmembrane region 4. The resultant transporter is non-functional.

Figure 3

The chloride bicarbonate transporter SLC26A3 in an intestinal epithelial cell. The SLC26A3 transporter is located on the apical surface of intestinal epithelial cells. It exchanges Cl⁻ from the intestinal lumen with HCO₃⁻. The transporter is indirectly coupled to the sodium hydrogen exchanger (NHE3) along the gastrointestinal (GI) tract. The Na⁺/K⁺ ATP pump establishes the necessary electrochemical gradient that eases this exchange. In congenital chloride diarrhoea, the SLC26A3 protein is dysfunctional; therefore, the intestinal epithelial cell cannot absorb Cl⁻ from the GI lumen and HCO₃⁻ is retained in the blood. This leads to a watery and Cl⁻ rich diarrhoea. The end result is severe hypochloraemia, hyponatraemia, metabolic alkalosis and hypokalaemia due to contraction alkalosis and activation of the renin-angiotensin-aldosterone system.