SEVERE POIKILOCYTOSIS ASSOCIATED WITH A DENOVO ALPHA-28 ARG-]CYS MUTATION IN SPECTRIN

Severe poikilocytosis was observed in an Italian child. The mutation responsible was a de novo alpha28 Arg --> Cys substitution (CGT --> TGT) in spectrin, a mutation known to cause hereditary elliptocytosis or hereditary pyropoikilocytosis. In this particular case the severity of the manifestations were accounted for by the occurrence, in trans to the alpha28 mutation, of the alpha(V/41) polymorphism. The latter has been shown previously to be associated with structural abnormalities at the alphaIV-alphaV domain junction and with a low expression level. The pronounced alteration of the dimer self association process was also explained by the location of the alpha28 mutation. This mutation occurs in helix 3 of repeating segment alpha1, e.g. precisely in the head-to-head contact between the spectrin alpha and beta chains. The present phenotype was compared to that yielded by another alpha28 mutation (Arg --> His) also combined, in trans, with the alpha(V/41) polymorphism. The pictures were very much alike, stressing the functional importance of residue alpha28. The de novo character of the present mutation strengthens the view that codon alpha28 is a 'hot spot' for mutations.