COMBINATION OF 2 MUTANT ALPHA-SPECTRIN ALLELES UNDERLIES A SEVERE SPHEROCYTIC HEMOLYTIC-ANEMIA

We studied a patient with a severe spherocytic hemolytic anemia withou t family history of spherocytosis, Analysis of patient's erythrocyte m embrane proteins revealed spectrin deficiency and a truncated alpha sp ectrin protein, We determined that the patient is a compound heterozyg ote with two mutations in alpha spectrin gene, Mutation in the paterna l allele, designated alpha spectrin(PRAGUE), is a transition A to G in the penultimate position of intron 36 that leads to skipping of exon 37, frameshift, and production of the truncated a spectrin protein. Th e maternal allele, designated a spectrin(LEPRA), contains transition C -->T in position -99 of intron 30, This mutation enhances an alternati ve acceptor splice site 70 nucleotides upstream from the regular site, The alternative splicing causes a frameshift and premature terminatio n of translation leading to a significant decrease in alpha spectrin p roduction, The alpha(LEPRA) mutation is linked to a spectrin alpha IIa marker that was found to be associated with recessive or nondominant spectrin-deficient hereditary spherocytosis in similar to 50% of studi ed families, We conclude that the alpha(LEPRA) mutation combined in tr ans with the alpha(PRAGUE) mutation underlie the severe hemolytic anem ia in the proband. We suggest that allele alpha spectrin(LEPRA) may be frequently involved in pathogenesis of recessive or nondominant spect rin-deficient hereditary spherocytosis.