HCO3--independent conductance with a mutant Na+/HCO3-cotransporter (SLC4A4) in a case of proximal renal tubular acidosis with hypokalaemic paralysis

Key points A mutant electrogenic sodium bicarbonate cotransporter NBCe1 (A799V) is associated with an inability of the kidney to regulate blood pH as well as weakness of muscles. In the present study we employ biotinylation and electrophysiology on Xenopus oocytes as well as confocal microscopy on non-polarized MDCK cells. We study A799V, plus three laboratory-generated mutants A799G, A799I and A799S. A799V and A799I show increased intracellular retention in MDCK cells. All four mutants exhibit a reduced per-molecule Na+/HCO3- cotransport activity in oocytes. These observations probably underlie the inability of A799V to regulate blood pH. A799V and A799I exhibit a novel, DIDS-stimulated, HCO3--independent conductance the first example in an electrogenic NBC. This observation could underlie the contribution of A799V towards muscle weakness. A799G and A799S exhibit unusual outward rectification. A799G is unusually insensitive to DIDS and tenidap. Thus Alanine-799 is a critical determinant of correct NBCe1 function.