title: A nonsense mutation 1669Glu-->Ter within the regulatory domain of human erythroid ankyrin leads to a selective deficiency of the major ankyrin isoform (band 2.1) and a phenotype of autosomal dominant hereditary spherocytosis.
abstract: We describe a nonsense mutation in the regulatory domain of erythroid ankyrin associated with autosomal dominant hereditary spherocytosis with a selective deficiency of the ankyrin isoform 2.1 (55% of normal), a deficiency of spectrin (58% of normal) proportional to the decrease in ankyrin 2.1, and a normal content of the other main ankyrin isoform, protein 2.2. PCR amplification of cDNA encoding the regulatory domain of ankyrin revealed a marked decreased in the ratio of ankyrin 2.1 mRNA to the ankyrin 2.2 mRNA. Sequencing of ankyrin gene in the region where the 2.1 and 2.2 mRNA differ detected a nonsense mutation 1669Glu-->Ter (GAA-->TAA) in one ankyrin allele. Only normal ankyrin 2.1 mRNA was detected in the reticulocyte RNA. Since the alternative splicing within the regulatory domain of ankyrin retains codon 1669 in ankyrin 2.1 mRNA and removes it from ankyrin 2.2 mRNA, we propose that the 1669Glu-->Ter mutation decreases the stability of the abnormal ankyrin 2.1 mRNA allele leading to a decreased synthesis of ankyrin 2.1 and a secondary deficiency of spectrin.
authors.affiliation: Department of Biomedical Research, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135.
authors.forename: P
authors.initials: P
authors.lastname: Jarolim
authors.forename: H L
authors.initials: HL
authors.lastname: Rubin
authors.forename: V
authors.initials: V
authors.lastname: Brabec
authors.forename: J
authors.initials: J
authors.lastname: Palek
mesh_terms: D000015:Abnormalities, Multiple; D000483:Alleles; D017398:Alternative Splicing; D017487:Ankyrins / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D004910:Erythrocyte Membrane / Q000737:chemistry; D004913:Erythrocytes, Abnormal / Q000737:chemistry* / Q000166:cytology*; D005799:Genes, Dominant / Q000235:genetics; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007567:Jaundice, Neonatal; D008969:Molecular Sequence Data; D009154:Mutation; D009996:Osmotic Fragility; D012333:RNA, Messenger / Q000235:genetics; D013049:Spectrin / Q000172:deficiency
chemical_list: C110202:ANK1 protein, human; D017487:Ankyrins; D012333:RNA, Messenger; D013049:Spectrin; D018698:Glutamic Acid