We investigated the properties of four dRTA-associated AE1 mutations (R589H, G609R, S613F, and G701D) by heterologous expression in Xenopus laevis oocytes.
We compared the effect of two dominant (R589H and S613F) and two recessive (S773P and G701D) dRTA point mutations on kAE1 trafficking in Madin-Darby canine kidney (MDCK) epithelial cells.
The absence of detectable AE1 polypeptide in those intercalated cells supports the genetic prediction that the AE1 R589H mutation indeed causes dominant dRTA.
Three different mutations at this position (R589C, R589H, and R589S) were all found in AD dRTA and a de novo R589H mutation has previously been recorded.
Thus, in contrast to previously described heterozygous loss-of-function mutations in AE1 associated with red cell abnormalities and apparently normal renal acidification, the heterozygous hypomorphic AE1 mutation R589H is associated with dominant dRTA and normal red cells.