Spectrin St Claude, a Splicing Mutation of the Human α-Spectrin Gene Associated With Severe Poikilocytic Anemia

Abstract

AbstractAn α-spectrin variant with increased susceptibility to tryptic digestion, αII/47, was previously observed in a child with severe, recessively inherited, poikilocytic anemia. The molecular basis of this variant, spectrin St Claude, has now been identified as a splicing mutation of the α-spectrin gene due to a T → G mutation in the 3′ acceptor splice site of exon 20. This polypyrimidine tract mutation creates a new acceptor splice site, AT → AG, and leads to the production of two novel mRNAs. One mRNA contains a 12 intronic nucleotide insertion upstream of exon 20. This insertion introduces a termination codon into the reading frame and is predicted to encode a truncated protein (108 kD) that lacks the nucleation site and thus cannot be assembled in the membrane. In the other mRNA, there is in-frame skipping of exon 20, predicting a truncated (277 kD) α-spectrin chain. The homozygous propositus has only truncated 277 kD α-spectrin chains in his erythrocyte membranes. His heterozygous parents are clinically and biochemically normal. This allele was identified in 3% of asymptomatic individuals from Benin, Africa.