title: A novel splicing mutation of the alpha-spectrin gene in the original hereditary pyropoikilocytosis kindred.
abstract: 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 alpha-spectrin (L207P) and an alpha-spectrin allele associated with a defect in alpha-spectrin production. To identify the molecular defect in the production-defective allele, reticulocyte alpha-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 alpha-spectrin gene transcripts derived from a minigene containing the IVS 22 +5 mutation.
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Costa
authors.forename: Larisa
authors.initials: L
authors.lastname: Lozovatsky
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Gallagher
authors.forename: Bernard G
authors.initials: BG
authors.lastname: Forget
mesh_terms: D000483:Alleles; D000743:Anemia, Hemolytic / Q000235:genetics* / Q000473:pathology; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D005091:Exons / Q000235:genetics; D015870:Gene Expression; D006579:Heterozygote; D006801:Humans; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013049:Spectrin / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D013049:Spectrin