Modulation of Clinical Expression and Band 3 Deficiency in Hereditary Spherocytosis

Abstract

AbstractWe present two novel alleles of the anion-exchanger 1 (AE1) gene, allele Coimbra and allele Mondego. Allele Coimbra (V488M, GTG → ATG) affects a conserved position in the putative second ectoplasmic loop of erythrocyte band 3. In 15 simple heterozygotes, it yielded a mild form of hereditary spherocytosis (HS) with band 3 deficiency (−20% ± 2%) and a reduced number of 4,4′-diisothiocyano-1,2-diphenylethane-2,2′-disulfonate (H2DIDS) binding sites (−35%). However, two additional heterozygotes presented with an aggravated HS and a more pronounced reduction of band 3 (−40%) and of H2DIDS binding sites (−48%). They carried, in trans to allele Coimbra, allele Mondego, defined by two mutations: E40K, GAG → AAG, the known mutation Montefiore, and P147S, CCT → TCT, a novel mutation, both located in the cytoplasmic domain of band 3. Allele Mondego itself resulted in no clinical or hematologic HS signs in the simple heterozygous state. Yet it yielded a slight decrease in band 3 (−6% to −12%) and in the number of H2DIDS binding sites (−19%). Thus, the more pronounced decrease in band 3 in the two compound heterozygotes derived from the additive effects of two unequally expressed AE1 alleles, resulting in a more severe clinical picture.