dRTA and hemolytic anemia: first detailed description of SLC4A1 A858D mutation in homozygous state

Abstract

Mutations in the anion exchanger 1 (AE1) gene encoding the erythroid and kidney anion (chloride-bicarbonate) exchanger 1 may result in familial distal renal tubular acidosis (dRTA) in association with membrane defect hemolytic anemia. Seven children presenting with hyperchloremic normal anion gap metabolic acidosis, failure to thrive, and compensated hemolytic anemia were studied. Analysis of red cell AE1/Band 3 surface expression by Eosin 5'-maleimide (E5M) was performed in patients and their family members using flow cytometry. Genetic studies showed that all patients carried a common SLC4A1 mutation, c.2573C>A; p.Ala858Asp in exon 19, found as homozygous (A858D/A858D) mutation in the patients and heterozygous (A858D/N) in the parents. Analysis by flowcytometry revealed a single uniform fluorescence peak, with the mean channel fluorescence (MCF) markedly reduced in cases with homozygous mutation, along with a left shift of fluorescence signal but was only mildly reduced in the heterozygous state. Red cell morphology showed striking acanthocytosis in the homozygous state [patients] and only a mild acanthocytosis in heterozygous state [parents]. In conclusion, this is the first description of a series of homozygous cases with the A858D mutation. The E5M flowcytometry test is specific for reduction in the Band 3 membrane protein and was useful in conjunction with a careful morphological examination of peripheral blood smears in our patient cohort.

Band 3 nullVIENNA, a novel homozygous SLC4A1 p.Ser477X variant causing severe hemolytic anemia, dyserythropoiesis and complete distal renal tubular acidosis

“…Omani Arab members of a consanguineous family with compensated dyserythropoietic ovalocytosis. 10 We identified a new homozygous exon 12 mutation in a now 5-year-old Turkish male with transfusion-dependent hemolytic anemia, dyserythropoiesis, and complete dRTA. We compare this new band 3 null patient (band 3 null VIENNA ) with the previous band 3 null COIMBRA patient 5,11 and provide an update on the progress of the female Coimbra patient.…”

“…However, mutations causing severe loss of anion exchange function in red cells are rare and usually lethal. Thus, only 15 homozygous individuals from seven families with severe forms of hemolytic anemia with and without dyserythropoiesis and complete dRTA have been reported so far: a Comorian patient with South‐east Asian ovalocytosis (SAO) and an exon 11 p.400‐408 deletion, an infant with spherocytosis and an exon 13 p.V488M COIMBRA mutation, an Italian patient with spherocytosis and a single base substitution NC_000017.11:g.44262850T>C NEAPOLIS in the donor splice site of intron 2, an Algerian patient with spherocytosis and an exon 16 p.S667F COURCOURONNES mutation, and 11 individuals with an exon 19 p.Ala858Asp mutation: two Indian patients with ovalocytosis, Indian twins of nonconsanguineous parents with spherocytosis, and seven Omani Arab members of a consanguineous family with compensated dyserythropoietic ovalocytosis …”

Chorein sensitivity of cytoskeletal organization and degranulation of platelets

“…In affected patients, the protein is either absent or nonfunctional (2). Heterozygous individuals may develop mild acanthocytosis (7).…”

Primary Autosomal Recessive Distal Renal Tubular Acidosis Caused by a Common HomozygousSLC4A1Mutation in Two Lao Families

“…The p.Ala858Asp mutation is geographically widespread, and cases have been reported not only from Southeast Asia, but also from Oman, India, and Papua New Guinea. 13 14 In contrast, the ΔVal850 mutation is confined to Papua New Guinea.…”

“… 6 AR dRTA caused by SLC4A1 mutations have been reported mostly from tropical Southeast Asia and other tropical areas, therefore called as tropical recessive dRTA. 7 8 9 10 11 12 13 14 15 Here, we report three Lao patients from two unrelated families with AR dRTA in association with the same homozygous SLC4A1 mutation, p.Gly701Asp.…”