β spectrin PRAGUE : a truncated β spectrin producing spectrin deficiency, defective spectrin heterodimer self‐association and a phenotype of spherocytic elliptocytosis

Summary. Spherocytic elliptocytosis is a phenotypic hybrid between hereditary spherocytosis (HS) and hereditary elliptocytosis (HE) characterized by the presence of spheroovalocytes and spherocytes which exhibit increased osmotic fragility, indicating a deficiency of surface area. Both the 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. Here we describe two members of a family who both have the characteristic features of spherocytic HE. We show that the underlying defect involves a G to C transversion at the ‐1 position of the acceptor splice site upstream of exon X of β spectrin leading to skipping of exon X from the mutant β 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 β spectrin, a finding which is likely to underlie the moderately severe spectrin deficiency in the two patients. In addition, this mutant spectrin, similar to the previously reported spectrins, is defective in spectrin heterodimer self‐association. The spectrin deficiency, which represents a common finding in the majority of patients with HS, together with weakened spectrin heterodimer self‐association, as found in the majority of patients with common HE, provides a molecular explanation for the phenotype of spherocytic elliptocytosis in this kindred and, most likely, in other patients carrying similar β spectrin mutations.