BETA-SPECTRIN(PRAGUE) - A TRUNCATED BETA-SPECTRIN PRODUCING SPECTRIN DEFICIENCY, DEFECTIVE SPECTRIN HETERODIMER SELF-ASSOCIATION AND A PHENOTYPE OF SPHEROCYTIC ELLIPTOCYTOSIS

Spherocytic elliptocytosis is a phenotypic hybrid between hereditary s pherocytosis (HS) and hereditary elliptocytosis (HE) characterized by the presence of spheroovalocytes and spherocytes which exhibit increas ed osmotic fragility, indicating a deficiency of surface area. Both th e spherocytic red cell morphology and the increased osmotic fragility distinguish this clinical entity from common HE. In contrast to common HE, the molecular basis of spherocytic elliptocytosis is unknown. Her e we describe two members of a family who both have the characteristic features of spherocytic HE. We show that the underlying defect involv es a G to C transversion at the -1 position of the acceptor splice sit e upstream of exon X of beta spectrin leading to skipping of exon X fr om the mutant beta spectrin mRNA allele. The mutant mRNA is present in reticulocytes in similar amounts as the normal mRNA. Pulse-labelling of erythroblasts prepared from peripheral blood in a two-phase liquid- culture system reveals a decreased synthesis of the truncated beta spe ctrin, a finding which is likely to underlie the moderately severe spe ctrin deficiency in the two patients. In addition, this mutant spectri n, similar to the previously reported spectrins, is defective in spect rin heterodimer self-association. The spectrin deficiency, which repre sents a common finding in the majority of patients with HS, together w ith weakened spectrin heterodimer self-association, as found in the ma jority of patients with common HE, provides a molecular explanation fo r the phenotype of spherocytic elliptocytosis in this kindred and, mos t likely, in other patients carrying similar beta spectrin mutations.