Dominant and Recessive Distal Renal Tubular Acidosis Mutations of Kidney Anion Exchanger 1 Induce Distinct Trafficking Defects in MDCK Cells

摘要: Distal renal tubular acidosis (dRTA), a kidney disease resulting in defective urinary acidification, can be caused by dominant or recessive mutations the Cl-/HCO3- anion exchanger (kAE1), glycoprotein expressed basolateral membrane of alpha-intercalated cells. We compared effect two (R589H and S613F) (S773P G701D) dRTA point on kAE1 trafficking Madin-Darby canine (MDCK) epithelial In contrast to wild-type (WT) that was localized membrane, mutants (kAE1 R589H were retained endoplasmic reticulum (ER) MDCK cells, with few cells showing addition some apical localization. The mutant S773P, while misfolded largely ER non-polarized targeted after polarization. other mutants, G701D designed G701E, G701R but not G701A G701L Golgi both polarized results suggest introduction polar mutation into transmembrane segment resulted retention mutant. When coexpressed, WT intracellularly, did not. Coexpression S773P showed these proteins could interact, yet no detected at membrane. Therefore, compound heterozygous patients expressing (G701D/S773P) likely developed due lack functional surface