title: Haplotype analysis and Agamma gene polymorphism associated with the Brazilian type of hereditary persistence of fetal hemoglobin.
abstract: We have identified three unrelated individuals and three members of a family with the non-deletion form of Agamma-hereditary persistence of fetal hemoglobin (HPFH). Molecular analysis showed that each individual is a heterozygote for a previously described -195 Agamma (C-->G) mutation. The beta-globin gene cluster was studied using the polymerase chain reaction and related techniques. Haplotyping using nine restriction sites identified two closely related chromosomes with the -195Agamma mutation, differing only in a single site 3' to the beta-globin gene. Further analysis of beta-globin framework indicated that the HPFH allele segregates with haplotype V, according to Orkin's classification. The second haplotype probably originated by a point mutation or DNA rearrangement of a pre-existing -195Agamma chromosome. We also determined the sequences from -622 to +55 bp upstream to the Agamma gene and part of the Agamma IVS-2. We found four polymorphisms associated to the -195Agamma promoter region. All -195Agamma chromosomes had a G at positions -588 and +25 relative to the Agamma gene. One individual was also homozygous for polymorphisms at -398 (G-->A), and another at -369 (C-->G). Cloning and sequencing of the polymorphic patterns of the 3' region of Agamma IVS-2 showed that the mutated allele is linked to beta-globin chromosome B. Some correlations between chromosome characteristics and Agamma point mutations were also observed.
authors.affiliation: Centro de Hematologia e Hemoterapia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, São Paulo, Brazil.
authors.forename: S
authors.initials: S
authors.lastname: Bordin
authors.forename: J T
authors.initials: JT
authors.lastname: Martins
authors.forename: M S
authors.initials: MS
authors.lastname: Gonçalves
authors.forename: M B
authors.initials: MB
authors.lastname: Melo
authors.forename: S T
authors.initials: ST
authors.lastname: Saad
authors.forename: F F
authors.initials: FF
authors.lastname: Costa
mesh_terms: D000328:Adult; D001483:Base Sequence; D001609:Beta-Globulins / Q000235:genetics; D002648:Child; D002874:Chromosome Mapping; D005260:Female; D005319:Fetal Hemoglobin / Q000235:genetics* / Q000378:metabolism*; D006239:Haplotypes / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*
chemical_list: D001609:Beta-Globulins; D005319:Fetal Hemoglobin