A NONSENSE MUTATION 1669GLU-]TER WITHIN THE REGULATORY DOMAIN OF HUMAN ERYTHROID ANKYRIN LEADS TO A SELECTIVE DEFICIENCY OF THE MAJOR ANKYRIN ISOFORM (BAND-2.1) AND A PHENOTYPE OF AUTOSOMAL-DOMINANT HEREDITARYSPHEROCYTOSIS

We describe a nonsense mutation in the regulatory domain of erythroid ankyrin associated with autosomal dominant hereditary spherocytosis wi th a selective deficiency of the ankyrin isoform 2.1 (55% of normal), a deficiency of spectrin (58% of normal) proportional to the decrease in ankyrin 2.1, and a normal content of the other main ankyrin isoform , protein 2.2. PCR amplification of cDNA encoding the regulatory domai n of ankyrin revealed a marked decrease in the ratio of ankyrin 2.1 mR NA to the ankyrin 2.2 mRNA. Sequencing of ankyrin gene in the region w here the 2.1 and 2.2 mRNA differ detected a nonsense mutation 1669Glu- ->Ter (GAA-->TAA) in one ankyrin allele. Only normal ankyrin 2.1 mRNA was detected in the reticulocyte RNA. Since the alternative splicing w ithin the regulatory domain of ankyrin retains codon 1669 in ankyrin 2 .1 mRNA and removes it from ankyrin 2.2 mRNA, we propose that the 1669 Glu-->Ter mutation decreases the stability of the abnormal ankyrin 2.1 mRNA allele leading to a decreased synthesis of ankyrin 2.1 and a sec ondary deficiency of spectrin.