Mutation Conferring Apical-Targeting Motif on AE1 Exchanger Causes Autosomal Dominant Distal RTA
| Autor: | Ya Su, Fiona E. Karet Frankl, Howard Trachtman, Alan W. Cuthbert, Vivian Yiu, Andrew C. Fry |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
Genotype PDZ domain Cell Amino Acid Motifs Xenopus Biology Kidney Cell Line Cell membrane Xenopus laevis Dogs Distal renal tubular acidosis stomatognathic system Clinical Research Anion Exchange Protein 1 Erythrocyte medicine Animals Humans Cells Cultured Epithelial polarity C-terminus Cell Membrane Wild type General Medicine Acidosis Renal Tubular medicine.disease biology.organism_classification Cell biology Pedigree stomatognathic diseases medicine.anatomical_structure Biochemistry Nephrology Models Animal Mutation Oocytes Female |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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