title: Fetal hemoglobin elevation in Hb Lepore heterozygotes and its correlation with beta globin cluster linked determinants.
abstract: We have analysed, at the hematological and molecular level, 51 Hb lepore heterozygotes and three compound heterozygotes for Hb Lepore and HbS (HbLep/HbS) in 26 unselected Portuguese families. The Lepore Boston variant was present in one family, in association with classical haplotype V. All of the other Lepore alleles present haplotype III in association with XmnI (+)5' of (G)gamma gene, in tight linkage disequilibrium to the major mutation found in the Portuguese population, the Lepore Baltimore variant ( delta(68Leu)-beta(84Thr)). The three compound heterozygotes are the first HbLep/HbS individuals reported in the literature, with the Lepore Baltimore mutation linked to haplotype III. In agreement with other studies, these Lepore Baltimore heterozygotes have higher HbF (1.4-14.1% of total hemoglobin) than published cases of Lepore Boston (0.8-5.4%), which is associated with XmnI(-). Among the Lepore Baltimore heterozygotes, the (AT)xTy repeat region at -540 bp of the beta globin gene in trans to the Lepore chromosome, can account for much of the variability in HbF level. The allele (AT)7T7 is associated with lower HbF, and (AT)9T5 is associated with higher HbF. As we previously reported for beta thalassemic carriers, we observe in Lepore Baltimore carriers an effector in trans, linked to the (AT)xTy sequence, acting as an HPFH (Hereditary Persistence of Fetal Hemoglobin) determinant.
authors.affiliation: Laboratório de Genética Molecular, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Caparica, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Gonçalves
authors.forename: Ana
authors.initials: A
authors.lastname: Henriques
authors.forename: Ana
authors.initials: A
authors.lastname: Raimundo
authors.forename: Isabel
authors.initials: I
authors.lastname: Picanço
authors.forename: Ana
authors.initials: A
authors.lastname: Reis
authors.forename: Esmeraldina
authors.initials: E
authors.lastname: Correia Junior
authors.forename: Ester
authors.initials: E
authors.lastname: Santos
authors.forename: Paulo
authors.initials: P
authors.lastname: Nogueira
authors.forename: Leonor
authors.initials: L
authors.lastname: Osório-Almeida
mesh_terms: D000293:Adolescent; D000328:Adult; D004247:DNA / Q000032:analysis; D004262:DNA Restriction Enzymes / Q000378:metabolism; D005319:Fetal Hemoglobin / Q000032:analysis*; D005914:Globins / Q000235:genetics*; D006239:Haplotypes; D006443:Hemoglobin A2 / Q000032:analysis; D006451:Hemoglobin, Sickle / Q000235:genetics*; D006455:Hemoglobins, Abnormal / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D012805:Sickle Cell Trait / Q000097:blood / Q000150:complications / Q000235:genetics
chemical_list: D006451:Hemoglobin, Sickle; D006455:Hemoglobins, Abnormal; D005914:Globins; D004247:DNA; D006443:Hemoglobin A2; D005319:Fetal Hemoglobin; C037659:hemoglobin Lepore; D004262:DNA Restriction Enzymes