title: The Hellenic type of nondeletional hereditary persistence of fetal hemoglobin results from a novel mutation (g.-109G>T) in the HBG2 gene promoter.
abstract: Nondeletional hereditary persistence of fetal hemoglobin (nd-HPFH), a rare hereditary condition resulting in elevated levels of fetal hemoglobin (Hb F) in adults, is associated with promoter mutations in the human fetal globin (HBG1 and HBG2) genes. In this paper, we report a novel type of nd-HPFH due to a HBG2 gene promoter mutation (HBG2:g.-109G>T). This mutation, located at the 3' end of the HBG2 distal CCAAT box, was initially identified in an adult female subject of Central Greek origin and results in elevated Hb F levels (4.1%) and significantly increased Ggamma-globin chain production (79.2%). Family studies and DNA analysis revealed that the HBG2:g.-109G>T mutation is also found in the family members in compound heterozygosity with the HBG2:g.-158C>T single nucleotide polymorphism or the silent HBB:g.-101C>T beta-thalassemia mutation, resulting in the latter case in significantly elevated Hb F levels (14.3%). Electrophoretic mobility shift analysis revealed that the HBG2:g.-109G>T mutation abolishes a transcription factor binding site, consistent with previous observations using DNA footprinting analysis, suggesting that guanine at position HBG2/1:g.-109 is critical for NF-E3 binding. These data suggest that the HBG2:g-109G>T mutation has a functional role in increasing HBG2 transcription and is responsible for the HPFH phenotype observed in our index cases.
authors.affiliation: Department of Biology, School of Medicine, University of Thessaly, Larissa, Greece.
authors.forename: Christos
authors.initials: C
authors.lastname: Chassanidis
authors.forename: Angelos
authors.initials: A
authors.lastname: Kalamaras
authors.forename: Marios
authors.initials: M
authors.lastname: Phylactides
authors.forename: Farzin
authors.initials: F
authors.lastname: Pourfarzad
authors.forename: Sophia
authors.initials: S
authors.lastname: Likousi
authors.forename: Vassilis
authors.initials: V
authors.lastname: Maroulis
authors.forename: Manoussos N
authors.initials: MN
authors.lastname: Papadakis
authors.forename: Nikolaos K
authors.initials: NK
authors.lastname: Vamvakopoulos
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Aleporou-Marinou
authors.forename: George P
authors.initials: GP
authors.lastname: Patrinos
authors.forename: Panagoula
authors.initials: P
authors.lastname: Kollia
mesh_terms: D000368:Aged; D005260:Female; D005319:Fetal Hemoglobin / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D005319:Fetal Hemoglobin