The Hellenic type of nondeletional hereditary persistence of fetal hemoglobin results from a novel mutation (g.-109G>T) in the gene promoter

Christos Chassanidis (1) , Angelos Kalamaras (1, 2) , Marios Phylactides (3) , Farzin Pourfarzad (4) , Sophia Likousi (1) , Vassilis Maroulis (5) , Manoussos N. Papadakis (6) , Nikolaos K. Vamvakopoulos (1) , Vassiliki Aleporou-Marinou (5) , George P. Patrinos (4) , Panagoula Kollia (1, 5)

1 Department of Biology, School of Medicine
2 Prevention Center of Thalassemia
3 Cyprus Institute of Neurology and Genetics
4 MGC-Department of Cell Biology and Genetics, Faculty of Medicine and Health Sciences
5 Department of Genetics and Biotechnology, Faculty of Biology, School of Physical Sciences
6 Center for Thalassemia, Unit of Prenatal Diagnosis

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 ( and ) genes. In this paper, we report a novel type of nd-HPFH due to a gene promoter mutation (:g.-109G>T). This mutation, located at the 3′ end of the 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 Gγ-globin chain production (79.2%). Family studies and DNA analysis revealed that the :g.-109G>T mutation is also found in the family members in compound heterozygosity with the :g.-158C>T single nucleotide polymorphism or the silent :g.-101C>T β-thalassemia mutation, resulting in the latter case in significantly elevated Hb F levels (14.3%). Electrophoretic mobility shift analysis revealed that the :g.-109G>T mutation abolishes a transcription factor binding site, consistent with previous observations using DNA footprinting analysis, suggesting that guanine at position :g.-109 is critical for NF-E3 binding. These data suggest that the :g-109G>T mutation has a functional role in increasing transcription and is responsible for the HPFH phenotype observed in our index cases.

Mots clés: Nondeletional hereditary persistence of fetal hemoglobin; β-thalassemia; Fetal globin genes; Mutation; Regulatory element; Transcription

Christos Chassanidis, Angelos Kalamaras, Marios Phylactides, Farzin Pourfarzad, Sophia Likousi, et al.. The Hellenic type of nondeletional hereditary persistence of fetal hemoglobin results from a novel mutation (g.-109G>T) in the gene promoter. Annals of Hematology, 2008, 88 (6), pp.549-555. ⟨10.1007/s00277-008-0643-0⟩. ⟨hal-00535006⟩