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.
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.
Jarolim
P
P
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
Shayakul
C
C
Prabakaran
D
D
Jiang
L
L
Stuart-Tilley
A
A
Rubin
H L
HL
Simova
S
S
Zavadil
J
J
Herrin
J T
JT
Brouillette
J
J
Somers
M J
MJ
Seemanova
E
E
Brugnara
C
C
Guay-Woodford
L M
LM
Alper
S L
SL
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
D001457:Anion Exchange Protein 1, Erythrocyte; D017920:Antiporters; D001639:Bicarbonates; D027963:Chloride-Bicarbonate Antiporters; D002712:Chlorides; D005819:Genetic Markers; D011994:Recombinant Proteins; D013431:Sulfates