A novel splicing mutation of the α-spectrin gene in the original hereditary pyropoikilocytosis kindred

DB Costa, L Lozovatsky, PG Gallagher, BG Forget - Blood, 2005 - ashpublications.org
DB Costa, L Lozovatsky, PG Gallagher, BG Forget
Blood, 2005ashpublications.org
Hereditary pyropoikilocytosis (HPP) is a severe hemolytic anemia due to abnormalities of
the red blood cell (RBC) membrane skeleton. In the original HPP kindred, there is
compound heterozygosity for an allele encoding a structural variant of α-spectrin (L207P)
and an α-spectrin allele associated with a defect in α-spectrin production. To identify the
molecular defect in the production-defective allele, reticulocyte α-spectrin cDNA from one of
the original HPP patients was analyzed. Transcripts from the production-defective, non …
Hereditary pyropoikilocytosis (HPP) is a severe hemolytic anemia due to abnormalities of the red blood cell (RBC) membrane skeleton. In the original HPP kindred, there is compound heterozygosity for an allele encoding a structural variant of α-spectrin (L207P) and an α-spectrin allele associated with a defect in α-spectrin production. To identify the molecular defect in the production-defective allele, reticulocyte α-spectrin cDNA from one of the original HPP patients was analyzed. Transcripts from the production-defective, non-L207P allele demonstrated a pattern of abnormal splicing between exons 22 and 23, resulting in insertion of intronic fragments with an in-frame premature termination codon. A G to A substitution at position +5 of the donor consensus splice site of IVS 22 was identified in the inserts. Following gene transfer into tissue culture cells, there was complete absence of normally spliced α-spectrin gene transcripts derived from a minigene containing the IVS 22 +5 mutation.
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