Combination of two mutant alpha spectrin alleles underlies a severe spherocytic hemolytic anemia

Abstract

We studied a patient with a severe spherocytic hemolytic anemia without family history of spherocytosis. Analysis of patient's erythrocyte membrane proteins revealed spectrin deficiency and a truncated α spectrin protein. We determined that the patient is a compound heterozygote with two mutations in α spectrin gene. Mutation in the paternal allele, designated α 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 α spectrin protein. The maternal allele, designated α spectrin-(LEPRA), contains transition C→T in position -99 of intron 30. This mutation enhances an alternative acceptor splice site 70 nucleotides upstream from the regular site. The alternative splicing causes a frameshift and premature termination of translation leading to a significant decrease in α spectrin production. The α(LEPRA) mutation is linked to a spectrin αIIa marker that was found to be associated with recessive or nondominant spectrin-deficient hereditary spherocytosis in ~50% of studied families. We conclude that the α(LEPRA) mutation combined in trans with the α(PRAGUE) mutation underlie the severe hemolytic anemia in the proband. We suggest that allele α spectrin(LEPRA) may be frequently involved in pathogenesis of recessive or nondominant spectrin-deficient hereditary spherocytosis.