title: A complex splicing defect associated with homozygous ankyrin-deficient hereditary spherocytosis.
abstract: Defects in erythrocyte ankyrin are the most common cause of typical, dominant hereditary spherocytosis (HS). Detection of ankyrin gene mutations has been complicated by allelic heterogeneity, large gene size, frequent de novo mutations, and associated mRNA instability. Using denaturing high-performance liquid chromatography (DHPLC)-based mutation detection, a mutation in the splice acceptor of exon 17 was discovered in a Turkish family. Reticulocyte RNA and functional minigene splicing assays in heterologous cells revealed that this mutation was associated with a complex pattern of aberrant splicing, suggesting that removal of intron 16 is important for ordered ankyrin mRNA splicing. As predicted by clinical, laboratory, and biochemical studies, the parents were heterozygous and the proband was homozygous for this mutation. These data indicate that DHPLC offers a highly sensitive, economic, and rapid method for mutation detection and, unlike previously suggested, homozygosity for a mutation associated with dominant ankyrin-linked HS may be compatible with life.
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520-8064, USA.
authors.forename: E Jennifer
authors.initials: EJ
authors.lastname: Edelman
authors.forename: Yelena
authors.initials: Y
authors.lastname: Maksimova
authors.forename: Feride
authors.initials: F
authors.lastname: Duru
authors.forename: Cigdem
authors.initials: C
authors.lastname: Altay
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Gallagher
mesh_terms: D017487:Ankyrins / Q000172:deficiency* / Q000235:genetics; D002851:Chromatography, High Pressure Liquid; D004252:DNA Mutational Analysis / Q000379:methods; D005091:Exons / Q000235:genetics; D005192:Family Health; D006720:Homozygote; D006801:Humans; D009154:Mutation; D012326:RNA Splicing / Q000235:genetics*; D013103:Spherocytosis, Hereditary / Q000209:etiology*; D014421:Turkey
chemical_list: D017487:Ankyrins