Anion exchanger 1 mutations associated with distal renal tubular acidosis in the Thai population

Abstract

We have previously demonstrated that compound heterozygous (SAO/G701D) and homozygous (G701D/G701D) mutations of the anion exchanger 1 (AE1) gene, encoding erythroid and kidney AE1 proteins, cause autosomal recessive distal renal tubular acidosis (AR dRTA) in Thai patients. It is thus of interest to examine the prevalence of these mutations in the Thai population. The SAO and G701D mutations were examined in 844 individuals from north, northeast, central, and south Thailand. Other reported mutations including R602H, DV850, and A858D were also examined in some groups of subjects. The SAO mutation was common in the southern Thai population; its heterozygote frequency was 7/206 and estimated allele frequency 1.70%. However, this mutation was not observed in populations of three other regions of Thailand. In contrast, the G701D mutation was not found in the southern population but was observed in the northern, northeastern, and central populations, with heterozygote frequencies of 1/216, 3/205, and 1/217, and estimated allele frequencies of 0.23%, 0.73%, and 0.23%, respectively. The higher allele frequency of the G701D mutation in the northeastern Thai population corresponds to our previous finding that all Thai patients with AR dRTA attributable to homozygous G701D mutation originate from this population. This suggests that the G701D allele that is observed in this region might arise in northeastern Thailand. The presence of patients with compound heterozygous SAO/G701D in southern Thailand and Malaysia and their apparently absence in northeastern Thailand indicate that the G701D allele may have migrated to the southern peninsular region where SAO is common, resulting in pathogenic allelic interaction.

Primary distal renal tubular acidosis: novel findings in patients studied by next-generation sequencing

“…NGS and posterior corroboration by Sanger sequencing revealed mutations in nine cases ( Table 2). Patients 122 and 323 harbor a missense change in SLC4A1 hotspot p.589 position (13,14) (R589C and R589H, respectively). Neither of their parents are mutation carriers, suggesting a de novo origin in both cases.…”

Cation transport activity of anion exchanger 1 mutations found in inherited distal renal tubular acidosis

“…Indeed, in Southeast Asian AE1-associated dRTA, including G701D, severe hypokalemia is more severe than European AE1-associated dRTA (5). G701D has a gene frequency of 0.7% in Northeastern Thailand (38), where dRTA is endemic (26), and hypokalemia with hypokalemic paralysis and sudden unexplained nocturnal death are common (25,27,28). However, whether the red cell abnormalities seen in the Southeast Asian AE1 mutations are associated with cation leak activity or whether hypokalemic disease in Northeastern Thailand is linked to G701D heterozygosity are questions that need addressing in future studies.…”

Recessive distal renal tubular acidosis in Sarawak caused by AE1 mutations

“…Thai researchers have established that the gene frequency of the G701D mutation in the population of Thailand [19] is 0.23-0.73% in the northern, northeastern and central parts of the country, but no G701D mutations were found in 206 individuals in the south of Thailand. Conversely, they found an allele frequency for the SAO mutation of 1.70% in the south of the country, but no instances of this mutation in the three other areas they studied.…”