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The Hellenic type of nondeletional hereditary persistence of fetal hemoglobin results from a novel mutation (g.-109G>T) in the HBG2 gene promoter.

Chassanidis C, Kalamaras A, Phylactides M, Pourfarzad F, Likousi S, Maroulis V, Papadakis MN, Vamvakopoulos NK, Aleporou-Marinou V, Patrinos GP, Kollia P - Ann. Hematol. (2008)

Bottom Line: 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%).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, School of Medicine, University of Thessaly, Larissa, Greece.

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.

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a DGGE analysis of the promoter region of the HBG2 gene. Numbering correlates with the family tree in Fig. 1a. Note the mutant HBG2:g.-158 T (lower band) and HBG2:g.-109 T homoduplexes (upper band) that comigrate in lanes II-2 and II-3, compared to lanes I-2 and II-1, respectively. The 40–70% denaturing gradient corresponds to the top and bottom of the gel, respectively. b DNA sequencing analysis, performed in the forward and reverse (not shown) orientation, revealing a G>T transition at position −109 of the HBG2 gene promoter (arrow)
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Fig2: a DGGE analysis of the promoter region of the HBG2 gene. Numbering correlates with the family tree in Fig. 1a. Note the mutant HBG2:g.-158 T (lower band) and HBG2:g.-109 T homoduplexes (upper band) that comigrate in lanes II-2 and II-3, compared to lanes I-2 and II-1, respectively. The 40–70% denaturing gradient corresponds to the top and bottom of the gel, respectively. b DNA sequencing analysis, performed in the forward and reverse (not shown) orientation, revealing a G>T transition at position −109 of the HBG2 gene promoter (arrow)

Mentions: During routine carrier screening for β-thalassemia, an adult female subject was identified with moderately elevated Hb F levels (4.1%) and significantly increased Gγ/Aγ-globin chain ratio (Fig. 1b). An aberrant electrophoretic pattern was identified during mutation screening in the HBG2 promoter by DGGE analysis (Fig. 2a). DNA sequencing of the proximal HBG2 promoter region revealed a novel sequence variation, namely, a G>T transversion at position −109 relative to the gene’s transcription initiation site (HBG2:g.-109G>T; Fig. 2b). DNA sequencing did not reveal any other variant nucleotide in either one of the γ-globin genes promoters and distal 5′ regulatory regions between positions −672 and +25. Neither the HBG2:g.-158C>T (XmnI) nor the HBG1:g.-225-222(AGCA)del polymorphisms, which are often correlated with moderately increased HbF levels, were found in the index case.Fig. 2


The Hellenic type of nondeletional hereditary persistence of fetal hemoglobin results from a novel mutation (g.-109G>T) in the HBG2 gene promoter.

Chassanidis C, Kalamaras A, Phylactides M, Pourfarzad F, Likousi S, Maroulis V, Papadakis MN, Vamvakopoulos NK, Aleporou-Marinou V, Patrinos GP, Kollia P - Ann. Hematol. (2008)

a DGGE analysis of the promoter region of the HBG2 gene. Numbering correlates with the family tree in Fig. 1a. Note the mutant HBG2:g.-158 T (lower band) and HBG2:g.-109 T homoduplexes (upper band) that comigrate in lanes II-2 and II-3, compared to lanes I-2 and II-1, respectively. The 40–70% denaturing gradient corresponds to the top and bottom of the gel, respectively. b DNA sequencing analysis, performed in the forward and reverse (not shown) orientation, revealing a G>T transition at position −109 of the HBG2 gene promoter (arrow)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2690858&req=5

Fig2: a DGGE analysis of the promoter region of the HBG2 gene. Numbering correlates with the family tree in Fig. 1a. Note the mutant HBG2:g.-158 T (lower band) and HBG2:g.-109 T homoduplexes (upper band) that comigrate in lanes II-2 and II-3, compared to lanes I-2 and II-1, respectively. The 40–70% denaturing gradient corresponds to the top and bottom of the gel, respectively. b DNA sequencing analysis, performed in the forward and reverse (not shown) orientation, revealing a G>T transition at position −109 of the HBG2 gene promoter (arrow)
Mentions: During routine carrier screening for β-thalassemia, an adult female subject was identified with moderately elevated Hb F levels (4.1%) and significantly increased Gγ/Aγ-globin chain ratio (Fig. 1b). An aberrant electrophoretic pattern was identified during mutation screening in the HBG2 promoter by DGGE analysis (Fig. 2a). DNA sequencing of the proximal HBG2 promoter region revealed a novel sequence variation, namely, a G>T transversion at position −109 relative to the gene’s transcription initiation site (HBG2:g.-109G>T; Fig. 2b). DNA sequencing did not reveal any other variant nucleotide in either one of the γ-globin genes promoters and distal 5′ regulatory regions between positions −672 and +25. Neither the HBG2:g.-158C>T (XmnI) nor the HBG1:g.-225-222(AGCA)del polymorphisms, which are often correlated with moderately increased HbF levels, were found in the index case.Fig. 2

Bottom Line: 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%).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, School of Medicine, University of Thessaly, Larissa, Greece.

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.

Show MeSH
Related in: MedlinePlus