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1 Department of Biochemistry, University of Bristol School of Medical Sciences, Bristol, United Kingdom
2 Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, United States
* To whom correspondence should be addressed. E-mail: mark.parker{at}yale.edu.
The human electrogenic renal Na/HCO3 cotransporter (NBCe1-A; SLC4A4) is localized to the basolateral membrane of proximal-tubule cells. Mutations in the SLC4A4 gene cause an autosomal recessive, proximal renal tubular acidosis (pRTA), a disease characterized by impaired ability of the proximal tubule to reabsorb HCO3- from the glomerular filtrate. Other symptoms can include mental retardation and ocular abnormalities. Recently, a novel homozygous missense mutant (R881C) of NBCe1-A was reported from a patient with a severe pRTA phenotype. The mutant protein was described as having a lower-than-normal activity when expressed in Xenopus oocytes, despite having normal Na+ affinity. However, without trafficking data, it is impossible to determine the molecular basis for the phenotype. In the present study, we expressed wild-type (WT) and mutant (R881C) NBCe1-A, tagged at the C-terminus with enhanced green fluorescent protein (EGFP). This approach permitted semi-quantification of surface expression in individual Xenopus oocytes prior to assay by two-electrode voltage-clamp or measurements of intracellular pH. These data show that the mutation reduces the surface expression rather that the activity of the individual protein molecules. Confocal microscopy on polarized mammalian epithelial kidney cells (MDCKI) expressing non-tagged WT or R881C demonstrate that WT is expressed at the basolateral membrane of these cells, whereas R881C is retained in the endoplasmic reticulum. In summary, the pathophysiology of pRTA caused by the R881C mutation is likely due to a deficit of NBCe1-A at the proximal-tubule basolateral membrane, rather than a defect in the transport activity of individual molecules.
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