BETA-SPECTRIN KISSIMMEE - A SPECTRIN VARIANT ASSOCIATED WITH AUTOSOMAL-DOMINANT HEREDITARY SPHEROCYTOSIS AND DEFECTIVE BINDING TO PROTEIN 4.1

We analyzed the DNA sequence of the cDNA encoding the NH2 terminal reg ion of beta spectrin from members of a kindred with autosomal dominant hereditary spherocytosis associated with defective protein 4.1 bindin g. We found a point mutation at codon 202 within the 272 amino acid NH 2-terminal region of beta-spectrin. TGG was changed to CGG, resulting in the replacement of tryptophan by arginine. The base change eliminat es a normally occurring PvuII restriction site and creates a new MspI site. This finding enabled rapid detection or exclusion of the mutatio n at the DNA level among the family members, including one member for whom this analysis was performed prenatally. The mutation was found on ly in the affected family members and occurred as a de novo mutation i n the proband. It has not been found in 20 other kindreds. The recombi nant peptide derived from the normal cDNA retains the capacity to sedi ment with protein 4.1 and F-actin. The mutant peptide spontaneously de grades. This variant represents both the first point mutation and the first beta spectrin mutation demonstrated in autosomal dominant heredi tary spherocytosis. Furthermore, the mutation is located within a cons erved sequence among spectrinlike proteins and may define an amino aci d critical for protein 4.1 binding activity.