title: Mutations in the chloride-bicarbonate exchanger gene AE1 cause autosomal dominant but not autosomal recessive distal renal tubular acidosis.
abstract: Primary distal renal tubular acidosis (dRTA) is characterized by reduced ability to acidify urine, variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. Kindreds showing either autosomal dominant or recessive transmission are described. Mutations in the chloride-bicarbonate exchanger AE1 have recently been reported in four autosomal dominant dRTA kindreds, three of these altering codon Arg589. We have screened 26 kindreds with primary dRTA for mutations in AE1. Inheritance was autosomal recessive in seventeen kindreds, autosomal dominant in one, and uncertain due to unknown parental phenotype or sporadic disease in eight kindreds. No mutations in AE1 were detected in any of the autosomal recessive kindreds, and analysis of linkage showed no evidence of linkage of recessive dRTA to AE1. In contrast, heterozygous mutations in AE1 were identified in the one known dominant dRTA kindred, in one sporadic case, and one kindred with two affected brothers. In the dominant kindred, the mutation Arg-589/Ser cosegregated with dRTA in the extended pedigree. An Arg-589/His mutation in the sporadic case proved to be a de novo mutation. In the third kindred, affected brothers both have an intragenic 13-bp duplication resulting in deletion of the last 11 amino acids of AE1. These mutations were not detected in 80 alleles from unrelated normal individuals. These findings underscore the key role of Arg-589 and the C terminus in normal AE1 function, and indicate that while mutations in AE1 cause autosomal dominant dRTA, defects in this gene are not responsible for recessive disease.
authors.affiliation: Howard Hughes Medical Institute, Departments of Medicine and Genetics, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: F E
authors.initials: FE
authors.lastname: Karet
authors.forename: F J
authors.initials: FJ
authors.lastname: Gainza
authors.forename: A Z
authors.initials: AZ
authors.lastname: Györy
authors.forename: R J
authors.initials: RJ
authors.lastname: Unwin
authors.forename: O
authors.initials: O
authors.lastname: Wrong
authors.forename: M J
authors.initials: MJ
authors.lastname: Tanner
authors.forename: A
authors.initials: A
authors.lastname: Nayir
authors.forename: H
authors.initials: H
authors.lastname: Alpay
authors.forename: F
authors.initials: F
authors.lastname: Santos
authors.forename: S A
authors.initials: SA
authors.lastname: Hulton
authors.forename: A
authors.initials: A
authors.lastname: Bakkaloglu
authors.forename: S
authors.initials: S
authors.lastname: Ozen
authors.forename: M J
authors.initials: MJ
authors.lastname: Cunningham
authors.forename: A
authors.initials: A
authors.lastname: di Pietro
authors.forename: W G
authors.initials: WG
authors.lastname: Walker
authors.forename: R P
authors.initials: RP
authors.lastname: Lifton
mesh_terms: D000141:Acidosis, Renal Tubular / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D017920:Antiporters / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D027963:Chloride-Bicarbonate Antiporters; D005260:Female; D005799:Genes, Dominant; D005808:Genes, Recessive; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation
chemical_list: D017920:Antiporters; D027963:Chloride-Bicarbonate Antiporters