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-589͞Ser cosegregated with dRTA in the extended pedigree. An Arg-589͞His 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.

A Novel Missense Mutation in the Sodium Bicarbonate Cotransporter (NBCe1/SLC4A4) Causes Proximal Tubular Acidosis and Glaucoma through Ion Transport Defects

“…In distal RTA (dRTA), the kidney fails to produce an appropriately acid urine in the presence of systemic metabolic acidosis or after acid loading, due to impaired hydrogen ion secretion in the distal nephron. Both autosomal dominant (OMIM 179800) (1)(2)(3)(4)(5) and autosomal recessive (OMIM 602722) (6, 7) patterns have been observed in kindreds with primary dRTA, and the spectrum of clinical severity is wide. Proximal RTA (pRTA) is caused by an impairment of bicarbonate absorption in the proximal tubule (PT) and is characterized by a decreased renal HCO 3 Ϫ threshold (8).…”

The B1-subunit of the H+ATPase is required for maximal urinary acidification

“…Human genetic studies have recently identified essential elements for pH homeostasis. To date, three genes in which mutations cause distal renal tubular acidosis have been identified (4)(5)(6). One of these genes, AE1, is essential for normal renal bicarbonate reabsorption.…”

Deficient HCO3- Transport in an AE1 Mutant with Normal Cl- Transport Can be Rescued by Carbonic Anhydrase II Presented on an Adjacent AE1 Protomer

“…Two families with dominant forms of dRTA have been reported to express distinct truncation mutations in the AE1 C-terminal tail (23,24). The AE1 901X mutation was associated with normal eAE1 polypeptide abundance and function in red cells, and exhibits wild-type (wt) Cl Ϫ influx in Xenopus oocytes (25), properties shared with the dominant dRTA AE1 mutant R589H (26,27).…”