Missense mutations and proximal RTA. Have we reached a new threshold? Focus on “Missense mutation T485S alters NBCe1-A electrogenicity causing proximal renal tubular acidosis”

Abstract

THE REABSORPTION OF BICARBONATE by the kidney requires parallel operation of apical transporters that secrete H and corresponding basolateral transporters that absorb bicarbonate. Approximately 80% to 90% of the filtered bicarbonate is reabsorbed in the proximal tubule, where secretion of H into HCO3 -rich glomerular filtrate by the Na/H exchanger, NHE-3, results in the formation of H2CO3 that is rapidly converted, within the tubule lumen, by membrane-bound carbonic anhydrase (type IV), to H2O and CO2, which can freely diffuse into the proximal tubule and, via intracellular carbonic anhydrase (type II), is converted to intracellular H2CO3 and HCO3 . Bicarbonate exits the cell via the electrogenic Na-3HCO3 symporter (NBCe1-A), with the negative cell potential serving as the primary driving force. This process is summarized in the proximal tubule cell model displayed in Fig. 1. Renal tubular acidosis (RTA) is a rare group of disorders whether inherited or acquired, although the incidence and prevalence are not well defined. The phenotype, when fully expressed, is recognized clinically as a chronic non-gap metabolic acidosis in the face of evidence of an inability of the kidney to excrete net acid appropriately, and is often associated with abnor