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

An a-spectrin variant with increased susceptibility to tryptic to encode a truncated protein (108 kD) that lacks the nucle-digestion, aII/47, was previously observed in a child with se- ation site and thus cannot be assembled in the membrane. vere, recessively inherited, poikilocytic anemia. The molecu- In the other mRNA, there is in-frame skipping of exon 20, lar basis of this variant, spectrin St Claude, has now been predicting a truncated (277 kD) a-spectrin chain. The homo-identified as a splicing mutation of the a-spectrin gene due zygous propositus has only truncated 277 kD a-spectrin to a T r G mutation in the 3 * acceptor splice site of exon 20. chains in his erythrocyte membranes. His heterozygous par-This polypyrimidine tract mutation creates a new acceptor ents are clinically and biochemically normal. This allele was splice site, AT r AG, and leads to the production of two identified in 3 % of asymptomatic individuals from Benin, novel mRNAs. One mRNA contains a 12 intronic nucleotide Africa. insertion upstream of exon 20. This insertion introduces a q 1997 by The American Society of Hematology. termination codon into the reading frame and is predicted T defect to the middle of the a-spectrin chain within the aIIdomain. In this report, we identify the underlying geneticHE SHAPE of the red blood cell, as well as its uniquemechanical properties, such as its remarkable deform-ability and prodigious stability under shear stress, depends defect in this individual, a polypyrimidine tract T r G muta-tion 13 nucleotides upstream of the 3 * acceptor splice siteon a multiprotein network, the membrane skeleton. The membrane skeleton is composed primarily of spectrin tetra- of exon 20 of the a-spectrin gene. This mutation abolishe