Purpose: The electrogenic Na+/HCO3- cotransporter (NBCe1) plays a major role in renal bicarbonate absorption via proximal tubules and therefore is crucial for maintaining normal blood pH. The human gene for NBCe1 (SLC4A4) produces two major transcripts by alternative promoter usage (kNBCe1, originally cloned from kidney and pNBCe1, pancreatic/general form). Though rare, recessive SLC4A4 mutations have been reported in patients with proximal renal tubular acidosis, short stature, and ocular pathology. A 27-year-old male presented with these findings. The purpose of this study was to investigate the molecular pathology responsible for this patient's clinical findings.
Methods: A comprehensive ophthalmic examination was performed, detailed ocular and systemic medical histories were taken and past medical records were obtained. Mutation screening was performed by using direct PCR sequencing of SLC4A4 exons and flanking intronic regions. Functional characterization of the mutation was made by expressing the wild-type and mutant NBCe1 proteins in Xenopus oocytes.
Results: We identified a novel, homozygous, missense SLC4A4 mutation (Leu522Pro in kNBCe1) in our patient who had pRTA, short stature, enamel hypoplasia, and bilateral ocular disease (cataract, glaucoma, and band keratopathy). The patient also had a medical history of ataxia, migraine with transient hemiparesis attacks, and slight hypothyroidism. The mutant RNA failed to induce electrogenic transport activity. The L522P-protein was not effectively transported to the oocyte membrane and thus was unable to act as a transmembrane transporter.
Conclusions: This novel mutation increases our understanding of the structural/functional aspects of the NBCe1 protein and the molecular basis of the multiorgan pathologies associated with its defects.