Nondominant hereditary spherocytosis (ndHS) is a disorder characterized in some patients by severe hemolytic anemia and marked deficiency of erythrocyte spectrin. This report describes the identification of a variant spectrin chain, ␣-spectrin Bughill or ␣ BH , that is associated with this disorder in a number of patients. Tryptic maps of spectrin from affected individuals revealed an acidic shift in isoelectric point of the ␣II domain peptides at 46 kD and 35 kD. A point mutation at codon 970 of the ␣-spectrin gene (GCT→GAT), that changes the encoded amino acid from an alanine to an aspartic acid, was identified in genomic DNA of affected patients. The ␣ BH variant was present in 8 patients with ndHS from five different kindreds but was absent in 4 patients from two other kindreds. The 8 ndHS patients with the ␣ BH variant appeared to be homozygous for the ␣ BH variant by analysis of peptide maps of limited tryptic digests of erythrocyte spectrin. However, following genomic DNA analysis, only 2 of these patients were true homozygotes, whereas 6 were found to be doubly heterozygous for the ␣ BH allele and a second, presumably abnormal, ␣-spectrin gene. These results suggest that, in these 6 patients, the second ␣-spectrin allele is in fact associated with one or more genetic defect(s), causing decreased accumulation of ␣-spectrin. The pattern of transmission of the ␣ BH allele in certain families suggests that the ␣ BH amino-acid substitution is not itself responsible for ndHS but is more likely a polymorphic variant that, in some but not all cases, is in linkage disequilibrium with another uncharacterized ␣-spectrin gene defect that itself is a cause of ndHS. Am.

We studied a French kindred with typical hereditary spherocytosis (

The genomic structure of a 1.5 kb region near the 5' end of the human erythrocyte band 3 gene (EPB3) was determined and the location of a two-allele PstI polymorphism in this region identified. Using this information, a polymerase chain reaction (PCR)-based assay was designed for rapid, simple identification of the PstI polymorphism.