Abstract
Congenital chloride diarrhea is an autosomal recessive disease caused by mutations in the intestinal lumenal membrane Cl−/HCO−3 exchanger, SLC26A3. We report here the novel SLC26A3 mutation G393W in a Mexican child, the first such report in a patient from Central America. SLC26A3 G393W expression in Xenopus oocytes exhibits a mild hypomorphic phenotype, with normal surface expression and moderately reduced anion transport function. However, expression of HA-SLC26A3 in HEK-293 cells reveals intracellular retention and greatly decreased steady-state levels of the mutant polypeptide, in contrast to peripheral membrane expression of the wildtype protein. Whereas wildtype HA-SLC26A3 is apically localized in polarized monolayers of filter-grown MDCK cells and Caco2 cells, mutant HA-SLC26A3 G393W exhibits decreased total polypeptide abundance, with reduced or absent surface expression and sparse punctate (or absent) intracellular distribution. The WT protein is similarly localized in LLC-PK1 cells, but the mutant fails to accumulate to detectable levels. We conclude that the chloride-losing diarrhea phenotype associated with homozygous expression of SLC26A3 G393W likely reflects lack of apical surface expression in enterocytes, secondary to combined abnormalities in polypeptide trafficking and stability. Future progress in development of general or target-specific folding chaperonins and correctors may hold promise for pharmacological rescue of this and similar genetic defects in membrane protein targeting.
Highlights
Congenital chloride diarrhea (CLD; OMIM# 214700) is a rare chronic secretory diarrhea of autosomal recessive inheritance associated with polyhydramnios and premature birth
At age 2 months he was hospitalized in a local Mexican hospital with acute diarrhea requiring intravenous rehydration therapy
We have presented a case of congenital chloride diarrhea (CLD) in a child in whom we have documented the novel SLC26A3 missense mutation G393W
Summary
Congenital chloride diarrhea (CLD; OMIM# 214700) is a rare chronic secretory diarrhea of autosomal recessive inheritance associated with polyhydramnios and premature birth. Postnatal clinical diagnosis is based on the presentation of dehydration and failure to thrive in the setting of hypokalemic metabolic alkalosis, with acidic stool pH and elevated stool chloride (>90 mM) measured after normalization of systemic volume status and serum electrolytes. Untreated disease leads to chronic systemic volume depletion, nephrocalcinosis and impaired renal function sometimes progressing to end-age renal disease. Additional clinical problems noted later in life have included intestinal inflammation, hyperuricemia, inguinal hernia, and impaired male fertility (Wedenoja et al, 2011). The single ∼2900 bp mRNA SLC26A3 transcript encodes a polypeptide of 764 amino acids (aa) in length. SLC26A3 mediates Cl−/HCO−3 exchange across the apical membrane of enterocytes, coordinating with Na+/H+ exchanger NHE3 (and in some conditions, NHE8, Xu et al, 2012) to carry out electroneutral NaCl reabsorption from the intestinal lumen (Zachos et al, 2005; Kato and Romero, 2011)
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