MODULATION OF CLINICAL EXPRESSION AND BAND-3 DEFICIENCY IN HEREDITARYSPHEROCYTOSIS

We present two novel alleles of the anion-exchanger 1 (AE1) gene, alle le Coimbra and allele Mondego. Allele Coimbra (V488M, GTG --> ATG) aff ects a conserved position in the putative second ectoplasmic loop of e rythrocyte 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 diisothiocyano-1,2-diphenylethane-2,2'-disulfo nate (H2DIDS) binding sites (-35%). However, two additional heterozygo tes presented with an aggravated HS and a more pronounced reduction of band 3 (-40%) and of H2DIDS binding sites (-48%). They carried, in tr ans 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. All ele Mondego itself resulted in no clinical or hematologic HS signs in the simple heterozygous state. Yet it yielded a slight decrease in ban d 3 (-6% to -12%) and in the number of H2DIDS binding sites (-19%). Th us, the more pronounced decrease in band 3 in the two compound heteroz ygotes derived from the additive effects of two unequally expressed AE 1 alleles, resulting in a more severe clinical picture. (C) 1997 by Th e American Society of Hematology.