title: Mutation conferring apical-targeting motif on AE1 exchanger causes autosomal dominant distal RTA.
abstract: Mutations in SLC4A1 that mislocalize its product, the chloride/bicarbonate exchanger AE1, away from its normal position on the basolateral membrane of the α-intercalated cell cause autosomal dominant distal renal tubular acidosis (dRTA). We studied a family exhibiting dominant inheritance and defined a mutation (AE1-M909T) that affects the C terminus of AE1, a region rich in potential targeting motifs that are incompletely characterized. Expression of AE1-M909T in Xenopus oocytes confirmed preservation of its anion exchange function. Wild-type GFP-tagged AE1 localized to the basolateral membrane of polarized MDCK cells, but AE1-M909T localized to both the apical and basolateral membranes. Wild-type AE1 trafficked directly to the basolateral membrane without apical passage, whereas AE1-M909T trafficked to both cell surfaces, implying the gain of an apical-targeting signal. We found that AE1-M909T acquired class 1 PDZ ligand activity that the wild type did not possess. In summary, the AE1-M909T mutation illustrates the role of abnormal targeting in dRTA and provides insight into C-terminal motifs that govern normal trafficking of AE1.
authors.affiliation: Department of Medical Genetics, University of Cambridge, United Kingdom.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Fry
authors.forename: Ya
authors.initials: Y
authors.lastname: Su
authors.forename: Vivian
authors.initials: V
authors.lastname: Yiu
authors.forename: Alan W
authors.initials: AW
authors.lastname: Cuthbert
authors.forename: Howard
authors.initials: H
authors.lastname: Trachtman
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Karet Frankl
mesh_terms: D000141:Acidosis, Renal Tubular / Q000235:genetics* / Q000378:metabolism; D020816:Amino Acid Motifs / Q000235:genetics*; D000818:Animals; D001457:Anion Exchange Protein 1, Erythrocyte / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004285:Dogs; D005260:Female; D005838:Genotype; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008297:Male; D023421:Models, Animal; D009154:Mutation / Q000235:genetics*; D009865:Oocytes / Q000378:metabolism; D010375:Pedigree; D014982:Xenopus laevis
chemical_list: D001457:Anion Exchange Protein 1, Erythrocyte