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: P Jarolim, C Shayakul, D Prabakaran, L Jiang, A Stuart-Tilley, H L Rubin, S Simova, J Zavadil, J T Herrin, J Brouillette, M J Somers, E Seemanova, C Brugnara, L M Guay-Woodford, S L Alper
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 273 Issue 11 Pg. 6380-8 (Mar 13 1998) ISSN: 0021-9258 [Print] United States
• PMID: 9497368 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anion Exchange Protein 1, Erythrocyte
• Antiporters
• Bicarbonates
• Chloride-Bicarbonate Antiporters
• Chlorides
• Genetic Markers
• Recombinant Proteins
• Sulfates

Topics

• Acidosis, Renal Tubular (etiology, genetics)
• Anion Exchange Protein 1, Erythrocyte (genetics)
• Antiporters (genetics)
• Bicarbonates (metabolism)
• Chloride-Bicarbonate Antiporters
• Chlorides (metabolism)
• Chromosomes, Human, Pair 17
• Erythrocytes (physiology)
• Female
• Genes, Dominant
• Genetic Linkage
• Genetic Markers
• Haplotypes
• Heterozygote
• Humans
• Male
• Microsatellite Repeats
• Mutation
• Phenotype
• Recombinant Proteins (metabolism)
• Sulfates (metabolism)