Proximal renal tubular acidosis and ocular pathology: a novelmissense mutation in the gene (SLC4A4) for sodium bicarbonatecotransporter protein (NBCe1)

[摘要] Purpose: The electrogenic Na+/HCO3- cotransporter(NBCe1) plays a major role in renal bicarbonate absorption via proximaltubules and therefore is crucial for maintaining normal blood pH. Thehuman gene for NBCe1 (SLC4A4) produces two major transcripts byalternative promoter usage (kNBCe1, originally cloned from kidney andpNBCe1, pancreatic/general form). Though rare, recessive SLC4A4mutations have been reported in patients with proximal renal tubularacidosis, short stature, and ocular pathology. A 27-year-old malepresented with these findings. The purpose of this study was toinvestigate the molecular pathology responsible for this patient'sclinical findings.Methods: A comprehensive ophthalmic examination was performed,detailed ocular and systemic medical histories were taken and pastmedical records were obtained. Mutation screening was performed by usingdirect PCR sequencing of SLC4A4 exons and flanking intronic regions.Functional characterization of the mutation was made by expressing thewild-type and mutant NBCe1 proteins in Xenopus oocytes.Results: We identified a novel, homozygous, missense SLC4A4mutation (Leu522Pro in kNBCe1) in our patient who had pRTA, shortstature, enamel hypoplasia, and bilateral ocular disease (cataract,glaucoma, and band keratopathy). The patient also had a medical historyof ataxia, migraine with transient hemiparesis attacks, and slighthypothyroidism. The mutant RNA failed to induce electrogenic transportactivity. The L522P-protein was not effectively transported to theoocyte membrane and thus was unable to act as a transmembranetransporter.Conclusions: This novel mutation increases our understanding of thestructural/functional aspects of the NBCe1 protein and the molecularbasis of the multiorgan pathologies associated with its defects.

[学科分类] 生物化学/生物物理