A novel missense mutation in the sodium bicarbonate cotransporter (NBCe1/SLC4A4) causes proximal tubular acidosis and glaucoma through ion transport defects

In humans and terrestrial vertebrates, the kidney controls systemic pH in part by absorbing filtered bicarbonate in the proximal tubule via an electrogenic Na⁺/HCO₃^- cotransporter (NBCe1/SLC4A4). Recently, human genetics revealed that NBCe1 is the major renal contributor to this process. Homozygous point mutations in NBCe1 cause proximal renal tubular acidosis (pRTA), glaucoma, and cataracts (Igarashi, T., Inatomi, J., Sekine, T., Cha, S. H., Kanai, Y., Kunimi, M., Tsukamoto, K., Satoh, H., Shimadzu, M., Tozawa, F., Mori, T., Shiobara, M., Seki, G., and Endou, H. (1999) Nat. Genet. 23, 264-266). We have identified and functionally characterized a novel, homozygous, missense mutation (S427L) in NBCe1, also resulting in pRTA and similar eye defects without mental retardation. To understand the pathophysiology of the syndrome, we expressed wild-type (WT) NBCe1 and 8427L-NBCe1 in Xenopus oocytes. Function was evaluated by measuring intracellular pH (HCO₃^- transport) and membrane currents using microelectrodes. HCO₃^--elicited currents for S427L were ∼10% of WT NBCe1, and CO₂-induced acidification was ∼4-fold faster. Na⁺-dependent HCO₃^- transport (currents and acidification) was also ∼10% of WT. Current-voltage (I-V) analysis reveals that S427L has no reversal potential in HCO ₃^-, indicating that under physiological ion gradient conditions, NaHCO₃ could not move out of cells as is needed for renal HCO₃^- absorption and ocular pressure homeostasis. I-V analysis without Na⁺ further shows that the S427L-mediated NaHCO ₃ efflux mode is depressed or absent. These experiments reveal that voltage- and Na⁺-dependent transport by S427L-hkN-BCe1 is unfavorably altered, thereby causing both insufficient HCO₃^- absorption by the kidney (proximal RTA) and inappropriate anterior chamber fluid transport (glaucoma).