Recessive distal renal tubular acidosis in Sarawak caused by AE1 mutations

Abstract

Mutations of the AE1 (SLC4A1, Anion-Exchanger 1) gene that codes for band 3, the renal and red cell anion exchanger, are responsible for many cases of familial distal renal tubular acidosis (dRTA). In Southeast Asia this disease is usually recessive, caused either by homozygosity of a single AE1 mutation or by compound heterozygosity of two different AE1 mutations. We describe two unrelated boys in Sarawak with dRTA associated with compound heterozygosity of AE1 mutations. Both had Southeast Asian ovalocytosis (SAO), a morphological abnormality of red cells caused by a deletion of band 3 residues 400-408. In addition, one boy had a DNA sequence abnormality of band 3 residue (G701D), which has been reported from elsewhere in Southeast Asia. The other boy had the novel sequence abnormality of band 3 (Q759H) and profound hemolytic anemia.

Distal Renal Tubular Acidosis in Filipino Children, Caused by Mutations of the Anion-Exchanger SLC4A1 (AE1, Band 3) Gene

“…The M31T mutation was also found in all the patients studied; this polymorphism is linked to the G701D mutation, and so all 7 patients were heterozygous for the mutation except patients 3 and 5a who were homozygous. Both M31T and K56E have been reported previously in association with G701D [2,3,4,6,7], are apparently innocuous and are common in oriental populations [16]. Because kidney band 3 lacks residues 1–65 of erythrocytic band 3, the M31T and K56E mutations in these children cannot be responsible for their dRTA, which must be caused by the G701D mutation, either in homozygous form or as a compound heterozygote with the Δ400–408 mutation.…”

“…Most patients were moderately anaemic at the time of diagnosis, with haemoglobin (Hb) values of 88–120 g/l (table 1), but other features of excess haemolysis, such as jaundice, reticulocytosis and splenomegaly were not noted. However, most children were receiving alkali treatment sufficient to correct acidosis at the time of follow-up visits to the clinic, so they did not show the increased tendency to haemolysis that has been observed in dRTA patients with AE1 mutations when they become seriously acidotic [7,14]. Patient 3, with G701D homozygosity, was unexpectedly found to be severely anaemic (Hb 58 g/l) when she attended the clinic aged 8 years, allegedly receiving her normal alkali medication but with a plasma bicarbonate of only 11 mmol/l.…”

“…We report here on 7 unrelated Filipino families with 9 dRTA children. An affected child from each family was found to have a band 3 mutation causing a substitution of the glycine in residue 701 by aspartic acid (G701D), a mutation already described in dRTA patients elsewhere in southeast Asia [3,5,6,7]. Children in 2 families were homozygous for this mutation, and those from the 5 other families were compound heterozygotes of G701D with the SAO 400–408 deletion.…”

“…SAO exists only in the heterozygous form; the homozygous form has never been reported, and is thought to be lethal to the fetus in utero [12]. SAO by itself does not cause defective urinary acidification [3,6], but many cases of dRTA have been described caused by compound heterozygosity of SAO with some other band 3 mutation affecting the opposite band-3 allele [3,5,6,7]. …”

“…This AE1 protein plays a vital role in tubular acid excretion, facilitating the return to body fluids of the bicarbonate generated by tubular proton secretion. Familial dRTA may be caused by homozygous mutations affecting this gene [2,3,4,5], or compound mutations affecting both alleles of the gene with different AE1 mutations [3,5,6,7]. Elsewhere in the world, familial dRTA may result from dominant mutations of this gene [8], or mutations affecting the H + -ATP-ase in the apical cell membrane or the carbonic anhydrase II of this cell [9], but these forms of inherited dRTA have rarely, if ever, been reported from Southeast Asia.…”