Mutations in SLC4A1 gene coding for kidney anion exchanger 1 (kAE1) cause distal renal tubular acidosis (dRTA). Here, we investigated the fate of the most common truncated dominant dRTA mutant, kAE1 R901X. In renal epithelial cells, we found that kAE1 R901X is less abundant at the plasma membrane than kAE1 wild-type (WT). Although both kAE1 WT and R901X had similar half-lives, the decreased abundance of kAE1 R901X at the surface is due to an increased endocytosis rate and decreased recycling rate of endocytosed proteins. We propose that in polarized renal epithelial cells, the apically mis-targeted kAE1 R901X mutant is endocytosed faster than kAE1 WT and has a delayed recycling to the basolateral membrane. This resets the equilibrium such that kAE1 R901X resides predominantly in an endomembrane compartment thereby causing dRTA disease.
- membrane protein
- distal renal tubular acidosis
- Copyright © 2016, American Journal of Physiology - Cell Physiology