Amino-acid substitution in α-spectrin commonly coinherited with nondominant hereditary spherocytosis

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, α-spectrin Bughill or α^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 αll domain peptides at 46 kD and 35 kD. A point mutation at codon 970 of the α-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 α^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 α^BH variant appeared to be homozygous for the α^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 α^BH allele and a second, presumably abnormal, α-spectrin gene. These results suggest that, in these 6 patients, the second α-spectrin allele is in fact associated with one or more genetic defect(s), causing decreased accumulation of α-spectrin. The pattern of transmission of the α^BH allele in certain families suggests that the α^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 α-spectrin gene defect that itself is a cause of ndHS. Am. J. Hematol. 54:233–241, 1997 © 1997 Wiley-Liss, Inc.