title: A common type of the spectrin alpha I 46-50a-kD peptide abnormality in hereditary elliptocytosis and pyropoikilocytosis is associated with a mutation distant from the proteolytic cleavage site. Evidence for the functional importance of the triple helical model of spectrin.
abstract: We studied nine individuals from five unrelated families with alpha I/46-50a hereditary elliptocytosis (HE) or hereditary pyropoikilocytosis (HPP), including one of the original HHP probands first reported by Zarkowsky and colleagues (1975. Br. J. Haematol. 29:537-543). Biochemical analysis of erythrocyte membrane proteins from these patients revealed, as a common abnormality, the presence of the alpha I/46-50a peptide after limited tryptic digestion of spectrin. The polymerase chain reaction was utilized to study the structure of the DNA encoding the alpha I domain of spectrin in the affected individuals. The DNA sequence of the alpha-spectrin gene encoding the region of the alpha-spectrin chain surrounding the abnormal proteolytic cleavage site was normal. We identified a point mutation causing the replacement of a highly conserved leucine residue by proline at position 207 in the alpha-spectrin chain, a site 51 residues to the amino-terminal side of the abnormal proteolytic cleavage site. Analysis of the proposed triple helical model of spectrin repeats reveals that the mutation occurs in helix 2 at a position directly opposite the abnormal proteolytic cleavage site in helix 3, making this the first report of a mutation occurring in helix 2 of a repeat in the alpha I domain of spectrin. These results add to the molecular heterogeneity of mutations associated with HE/HPP and provide further support for the proposed triple helical model of spectrin. Disruption of this proposed alpha-helical structure by helix-breaking proline substitutions may result in a functionally defective spectrin chain.
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06510.
authors.forename: P G
authors.initials: PG
authors.lastname: Gallagher
authors.forename: W T
authors.initials: WT
authors.lastname: Tse
authors.forename: T
authors.initials: T
authors.lastname: Coetzer
authors.forename: M C
authors.initials: MC
authors.lastname: Lecomte
authors.forename: M
authors.initials: M
authors.lastname: Garbarz
authors.forename: H S
authors.initials: HS
authors.lastname: Zarkowsky
authors.forename: A
authors.initials: A
authors.lastname: Baruchel
authors.forename: S K
authors.initials: SK
authors.lastname: Ballas
authors.forename: D
authors.initials: D
authors.lastname: Dhermy
authors.forename: J
authors.initials: J
authors.lastname: Palek
mesh_terms: D000595:Amino Acid Sequence; D000745:Anemia, Hemolytic, Congenital / Q000235:genetics*; D001483:Base Sequence; D004612:Elliptocytosis, Hereditary / Q000235:genetics*; D004907:Erythrocyte Deformability; D004913:Erythrocytes, Abnormal; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D011487:Protein Conformation; D013049:Spectrin / Q000032:analysis / Q000737:chemistry* / Q000235:genetics
chemical_list: D013049:Spectrin