title: Autosomal dominant distal renal tubular acidosis is associated in three families with heterozygosity for the R589H mutation in the AE1 (band 3) Cl-/HCO3- exchanger.
abstract: Distal renal tubular acidosis (dRTA) is characterized by defective urinary acidification by the distal nephron. Cl-/HCO3- exchange mediated by the AE1 anion exchanger in the basolateral membrane of type A intercalated cells is thought to be an essential component of lumenal H+ secretion by collecting duct intercalated cells. We evaluated the AE1 gene as a possible candidate gene for familial dRTA. We found in three unrelated families with autosomal dominant dRTA that all clinically affected individuals were heterozygous for a single missense mutation encoding the mutant AE1 polypeptide R589H. Patient red cells showed approximately 20% reduction in sulfate influx of normal 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid sensitivity and pH dependence. Recombinant kidney AE1 R589H expressed in Xenopus oocytes showed 20-50% reduction in Cl-/Cl- and Cl-/HCO3- exchange, but did not display a dominant negative phenotype for anion transport when coexpressed with wild-type AE1. One apparently unaffected individual for whom acid-loading data were unavailable also was heterozygous for the mutation. 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.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: P
authors.initials: P
authors.lastname: Jarolim
authors.forename: C
authors.initials: C
authors.lastname: Shayakul
authors.forename: D
authors.initials: D
authors.lastname: Prabakaran
authors.forename: L
authors.initials: L
authors.lastname: Jiang
authors.forename: A
authors.initials: A
authors.lastname: Stuart-Tilley
authors.forename: H L
authors.initials: HL
authors.lastname: Rubin
authors.forename: S
authors.initials: S
authors.lastname: Simova
authors.forename: J
authors.initials: J
authors.lastname: Zavadil
authors.forename: J T
authors.initials: JT
authors.lastname: Herrin
authors.forename: J
authors.initials: J
authors.lastname: Brouillette
authors.forename: M J
authors.initials: MJ
authors.lastname: Somers
authors.forename: E
authors.initials: E
authors.lastname: Seemanova
authors.forename: C
authors.initials: C
authors.lastname: Brugnara
authors.forename: L M
authors.initials: LM
authors.lastname: Guay-Woodford
authors.forename: S L
authors.initials: SL
authors.lastname: Alper
mesh_terms: D000141:Acidosis, Renal Tubular / Q000209:etiology / Q000235:genetics*; D001457:Anion Exchange Protein 1, Erythrocyte / Q000235:genetics*; D017920:Antiporters / Q000235:genetics*; D001639:Bicarbonates / Q000378:metabolism; D027963:Chloride-Bicarbonate Antiporters; D002712:Chlorides / Q000378:metabolism; D002886:Chromosomes, Human, Pair 17; D004912:Erythrocytes / Q000502:physiology; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D005819:Genetic Markers; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D009154:Mutation; D010641:Phenotype; D011994:Recombinant Proteins / Q000378:metabolism; D013431:Sulfates / Q000378:metabolism
chemical_list: D001457:Anion Exchange Protein 1, Erythrocyte; D017920:Antiporters; D001639:Bicarbonates; D027963:Chloride-Bicarbonate Antiporters; D002712:Chlorides; D005819:Genetic Markers; D011994:Recombinant Proteins; D013431:Sulfates