Autosomal recessive distal renal tubular acidosis caused by G701D mutation of anion exchanger 1 gene.

Anion exchanger 1 (AE1 or band 3), encoded by the AE1 or SLC4A1 gene, regulates chloride-bicarbonate exchange in erythrocytes and alpha-intercalated cells of the distal nephron. Defects of AE1 at the basolateral membrane of alpha-intercalated cells may result in the failure of hydrogen ion secretion at the apical membrane, leading to distal renal tubular acidosis (dRTA). Abnormalities of the AE1 gene were previously reported to be associated with autosomal dominant dRTA. However, recent studies of Thai dRTA families have shown that mutations in this gene result in autosomal recessive (AR) dRTA, giving rise to the postulation that AE1 gene mutations causing AR dRTA might be found commonly in Thai pediatric patients with dRTA. We performed a study of the AE1 gene using DNA linkage, polymerase chain reaction single-strand conformation polymorphism, restriction endonuclease HpaII digestion, and DNA sequence analyses in eight families involving 12 Thai children with dRTA, shown by abnormal urinary acidification using a short acid-loading test, as well as among their family members. Seven patients with dRTA from five families had the same homozygous missense G701D mutation of the AE1 gene. Their parents or siblings heterozygous for the AE1 G701D mutation were clinically normal and did not have abnormal urinary acidification, although a heterozygous sibling in one family had abnormal urinary acidification. Results of this and previous studies show that a homozygous AE1 G701D mutation causes AR dRTA and is a common molecular defect among Thai pediatric patients with dRTA.

A de novo R589C mutation of anion exchanger 1 causing distal renal tubular acidosis.

Anion exchanger 1 (AE1 or SLC4A1) mutations have been reported to cause distal renal tubular acidosis (dRTA), a disease characterized by impaired acid excretion in the distal nephron. We have recently demonstrated homozygous AE1 G701D mutation as a common molecular defect of autosomal recessive (AR) dRTA in a group of Thai pediatric patients. In the present work, we discovered a de novo heterozygous AE1 R589C mutation, previously documented in inherited autosomal dominant (AD) dRTA. Arginine at this position is conserved in all vertebrate AE proteins indicating its functional importance. Three different mutations at this position (R589C, R589H, and R589S) were all found in AD dRTA and a de novo R589H mutation has previously been recorded. Our report is the second de novo mutation but with a different substituted amino acid. A high prevalence of AE1 R589 mutations and the presence of at least two de novo mutations at this position lead us to propose that codon 589 (CGC) is a "mutational hotspot" of AE1. The mechanism of recurrent mutations probably involves methylation and deamination altering cytosine (C) to thymine (T) in the CpG dinucleotides.