AMINO-ACID SUBSTITUTION IN ALPHA-SPECTRIN COMMONLY COINHERITED WITH NONDOMINANT HEREDITARY SPHEROCYTOSIS

Nondominant hereditary spherocytosis (ndHS) is a disorder characterize d in some patients by severe hemolytic anemia and marked deficiency of erythrocyte spectrin. This report describes the identification of a v ariant spectrin chain, alpha-spectrin Bughill or alpha(BH), that is as sociated with this disorder in a number of patients. Tryptic maps of s pectrin from affected individuals revealed an acidic shift in isoelect ric point of the all domain peptides at 46 kD and 35 kD. A point mutat ion at codon 970 of the alpha-spectrin gene (GCT-->GAT), that changes the encoded amino acid from an alanine to an aspartic acid, was identi fied in genomic DNA of affected patients. The alpha(BH) variant was pr esent in 8 patients with ndHS from five different kindreds but was abs ent in 4 patients from two other kindreds. The 8 ndHS patients with th e alpha(BH) variant appeared to be homozygous for the alpha(BH) varian t by analysis of peptide maps of limited tryptic digests of erythrocyt e spectrin. However, following genomic DNA analysis, only 2 of these p atients were true homozygotes, whereas 6 were found to be doubly heter ozygous for the alpha(BH) allele and a second, presumably abnormal, al pha-spectrin gene. These results suggest that, in these 6 patients, th e second alpha-spectrin allele is in fact associated with one or more genetic defect(s), causing decreased accumulation of alpha-spectrin. T he pattern of transmission of the alpha(BH) allele in certain families suggests that the alpha(BH) amino-acid substitution is not itself res ponsible for ndHS but is more likely a polymorphic variant that, in so me but not all cases, is in linkage disequilibrium with another unchar acterized alpha-spectrin gene defect that itself is a cause of ndHS. ( C) 1997 Wiley-Liss, Inc.