title: Congenital chloride-losing diarrhea in a Mexican child with the novel homozygous SLC26A3 mutation G393W.
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.
authors.affiliation: Renal Division, Beth Israel Deaconess Medical Center Boston, MA, USA.
authors.forename: Fabian R
authors.initials: FR
authors.lastname: Reimold
authors.affiliation: Renal Division, Beth Israel Deaconess Medical Center Boston, MA, USA.
authors.forename: Savithri
authors.initials: S
authors.lastname: Balasubramanian
authors.affiliation: Renal Division, Beth Israel Deaconess Medical Center Boston, MA, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Doroquez
authors.affiliation: Renal Division, Beth Israel Deaconess Medical Center Boston, MA, USA.
authors.forename: Boris E
authors.initials: BE
authors.lastname: Shmukler
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center Boston, MA, USA ; Department of Pathology, Harvard Medical School Boston, MA, USA.
authors.forename: Zsuzsanna K
authors.initials: ZK
authors.lastname: Zsengeller
authors.affiliation: Division of Pediatric Gastroenterology, Boston Children's Hospital Boston, MA, USA ; Department of Pediatrics, Harvard Medical School Boston, MA, USA ; Harvard Digestive Diseases Center, Harvard Medical School Boston, MA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Saslowsky
authors.affiliation: Division of Pediatric Gastroenterology, Boston Children's Hospital Boston, MA, USA ; Department of Pediatrics, Harvard Medical School Boston, MA, USA ; Harvard Digestive Diseases Center, Harvard Medical School Boston, MA, USA.
authors.forename: Jay R
authors.initials: JR
authors.lastname: Thiagarajah
authors.affiliation: Renal Division, Beth Israel Deaconess Medical Center Boston, MA, USA ; Department of Pathology, Beth Israel Deaconess Medical Center Boston, MA, USA ; Department of Pathology, Harvard Medical School Boston, MA, USA.
authors.forename: Isaac E
authors.initials: IE
authors.lastname: Stillman
authors.affiliation: Division of Pediatric Gastroenterology, Boston Children's Hospital Boston, MA, USA ; Department of Pediatrics, Harvard Medical School Boston, MA, USA ; Harvard Digestive Diseases Center, Harvard Medical School Boston, MA, USA.
authors.forename: Wayne I
authors.initials: WI
authors.lastname: Lencer
authors.affiliation: Department of Pathology, Harvard Medical School Boston, MA, USA ; Genetics Diagnostic Laboratory and Claritas Genetics, Boston Children's Hospital Boston, MA, USA ; Children's Hospital and Institute of Biomedical Sciences of Fudan University Shanghai, China.
authors.forename: Bai-Lin
authors.initials: BL
authors.lastname: Wu
authors.affiliation: Department of Pediatric Gastroenterology and Nutrition, Hospital Infantil de Mexico Federico Gomez Mexico City, Mexico.
authors.forename: Salvador
authors.initials: S
authors.lastname: Villalpando-Carrion
authors.affiliation: Renal Division, Beth Israel Deaconess Medical Center Boston, MA, USA ; Harvard Digestive Diseases Center, Harvard Medical School Boston, MA, USA ; Department of Medicine, Harvard Medical School Boston, MA, USA.
authors.forename: Seth L
authors.initials: SL
authors.lastname: Alper
keywords: MDCK cells; NaCl reabsorption; Xenopus oocyte; chloride bicarbonate exchange; down-regulated in adenoma