MUTATIONS FOUND, IN THE PROMOTER REGION OF THE ?-GLOBIN GENE, IN ONLY ONE HOSPITAL IN MADRID.
(Abstract release date: 05/19/16)
EHA Library. Ropero P. 06/09/16; 135022; PB2122
Dr. Paloma Ropero
Contributions
Contributions
Abstract
Abstract: PB2122
Type: Publication Only
Background
The β+-thalassemia is characterized by reduced production of beta chains, which can be produced by mutations in the promoter area (either the CACCC or TATA box). Depending on the extent of reduction of beta globin chain, the β+-thalassemia mutations may be classified into mild and silent. Silent β-thalassemia is characterized in the heterozygous state by normal MCV and MCH, normal or more frequently borderline HbA2, and normal HbF. Globin chain synthesis ratio is only slightly imbalanced, and sometimes even normal. This phenotype may escape detection by the usual methods, so DNA study being necessary for proper identification. Compound heterozygosity of these mutations with a severe mutation always produces very mild thalassemia intermedia. Frequently the diagnosis is made in adulthood or even in the elderly. Mild β-thalassemia mutations are characterized by a residual high β-chain production, show moderate thalassemia-like hematological features and imbalance chain synthesis. This group of molecular defects includes transcriptional mutants in the proximal CACCC box and in the TATA box. Homozygotes or compound hetrozygotes for these mild mutations usually have thalassemia intermedia.So far a total of 37 alterations have been described in the promoter region, some of which are ethnic specific, -87 C>T are common in Mediterranean areas, while -29 A>G and -88 C>T are frequently found in blacks.
Aims
In this report we present a compilation of the mutations found, in the promoter region of the β-globin gene, in only one Hospital in Madrid.
Methods
The hematological parameters were determined with Coulter LH750 Analyzer. HbA2 and HbF levels, as well as the different hemoglobins, were measured and analyzed by ion-exchange HPLC (VARIANTTM II). Hemoglobins were studied by capillary zone electrophoresis (CE) (Sebia). Genetic analysis of the β and Gγ globin genes was carried out by automatic sequencing and, in the case of α genes, by multiplex PCR.
Results
Conclusion
All these mutations show the importance of the promoter region in the β globin genes. Except for the mutation located at the distal CACCC (-101 C> T) that presents a β-thalassemia silent, the rest behaves as a β-thalassemia mild, generally high levels of HbA2 HbF and being the cause most likely the partial removal of competitiveness to limit transcription factors, facilitating their access to the promoters of both genes as the δ γ genes. Thus, as seen, any alteration in the CACCC proximal box and the TATA box, cause a moderate decline in the synthesis of the β globin chain, which has been tested both cases of thalassemia intermedia that they made their debut in the second decade of life with a moderate clinical as when associated with a HbS where the disease is mild sickle cell anemia as there is a residual activity of 20% HbA. The identification of such mutations is important for a good genetic counseling that will provide information to individuals and couples at risk (both carriers) in relation to the mode of inheritance, the genetic risk of having affected children and history nature of the disease, including treatment and thus make an informed decision about their reproductive options.
Session topic: E-poster
Keyword(s): Thalassemia
Type: Publication Only
Background
The β+-thalassemia is characterized by reduced production of beta chains, which can be produced by mutations in the promoter area (either the CACCC or TATA box). Depending on the extent of reduction of beta globin chain, the β+-thalassemia mutations may be classified into mild and silent. Silent β-thalassemia is characterized in the heterozygous state by normal MCV and MCH, normal or more frequently borderline HbA2, and normal HbF. Globin chain synthesis ratio is only slightly imbalanced, and sometimes even normal. This phenotype may escape detection by the usual methods, so DNA study being necessary for proper identification. Compound heterozygosity of these mutations with a severe mutation always produces very mild thalassemia intermedia. Frequently the diagnosis is made in adulthood or even in the elderly. Mild β-thalassemia mutations are characterized by a residual high β-chain production, show moderate thalassemia-like hematological features and imbalance chain synthesis. This group of molecular defects includes transcriptional mutants in the proximal CACCC box and in the TATA box. Homozygotes or compound hetrozygotes for these mild mutations usually have thalassemia intermedia.So far a total of 37 alterations have been described in the promoter region, some of which are ethnic specific, -87 C>T are common in Mediterranean areas, while -29 A>G and -88 C>T are frequently found in blacks.
Aims
In this report we present a compilation of the mutations found, in the promoter region of the β-globin gene, in only one Hospital in Madrid.
Methods
The hematological parameters were determined with Coulter LH750 Analyzer. HbA2 and HbF levels, as well as the different hemoglobins, were measured and analyzed by ion-exchange HPLC (VARIANTTM II). Hemoglobins were studied by capillary zone electrophoresis (CE) (Sebia). Genetic analysis of the β and Gγ globin genes was carried out by automatic sequencing and, in the case of α genes, by multiplex PCR.
Results
| Hb (g/dL) | VCM (fL) | HCM (pg) | HbA2-HbF (%) | OTHER MUTATION | SEX/AGE | ETHNIC | |
| -27 (A>T) β+ [I] | 13.9 | 80.4 | 26.6 | 4.2-0.5 | M/39 | C | |
| -28 (A>G) β+IIIIIIVVVI | 6.46.88.913.913.0 | 71.072.573.575.877.3 | 21.321.525.724.325.1 | 1.9-98.02.0-97.52.7-27.94.9-0.94.4-1.1 | CD71/72 (+A) β0CD71/72 (+A) β0CD41/42 (-TTCT) β0 | F/2F/2M/5F/29F/23 | ChChChChCh |
| -29 (A>G) β+VIIVIIIIXXXIXIIXIIIXIVXVXVIXVIIXVIIIXIXXXXXIXXIIXXIII | 12.612.810.111.712.314.26.812.115.210.912.814.19.512.56.96.812.8 | 74.272.373.573.375.878.383.268.972.762.567.174.388.578.062.061.273.4 | 25.322.623.323.524.626.126.021.323.718.219.823.526.725.227.028.925.7 | 5.1-5.55.3-3.86.9-3.36.5-4.15.0-3.97.0-4.05.7-10.34.2-6.33.8-5.04.3-0.44.0-0.84.6-1.73.0-17.05.0-3.56.0-9.58.0-30.05.2-3.4 | -α3.7/αα-α3.7/αα-α3.7/αα-α3.7/αα-α3.7/αα-α3.7/αα + [HbS]-α3.7/αα + [HbS] IVS-2-nt843 (T>G) β+IVS-1-nt5 (C>G) β++ -29 (A>G)-29 (A>G) | M/31F/28M/20 F/21M/42M/33F/22M/25M/17F/44M/53M/23F/24M/26M/25F/20 | BBBBBBBCBBBCCBBBB |
| -56 (G>C) β+ [XXIV] | 13.0 | 72 | 23.5 | 5.3-4.1 | M/23 | B | |
| -86 (C>A) β+XXVXXVIXXVII | 15.211.815.3 | 67.371.973.2 | 22.322.124.9 | 3.6-6.03.5-1.63.2-2.0 | M/77F/30M/32 | CCC | |
| -88 (C>T) β+XXVIIIXXIXXXXXXXIXXXIIXXXIIIXXXIV | 11.813.113.313.211.012.412.4 | 76.971.872.373.666.173.772.7 | 23.623.322.923.222.123.724.2 | 5.3-5.75.9-5.65.3-3.45.6-2.95.2-15.84.1-4.16.0-10.0 | [HbS][HbS][HbS] | F/25F/39F/50F/20F/4M/27F/27 | BCCCBBB |
| -101 (C>T) β+ [XXXIV] | 11.3 | 72.5 | 23.9 | 3.8-1.5 | M/2 | B |
Conclusion
All these mutations show the importance of the promoter region in the β globin genes. Except for the mutation located at the distal CACCC (-101 C> T) that presents a β-thalassemia silent, the rest behaves as a β-thalassemia mild, generally high levels of HbA2 HbF and being the cause most likely the partial removal of competitiveness to limit transcription factors, facilitating their access to the promoters of both genes as the δ γ genes. Thus, as seen, any alteration in the CACCC proximal box and the TATA box, cause a moderate decline in the synthesis of the β globin chain, which has been tested both cases of thalassemia intermedia that they made their debut in the second decade of life with a moderate clinical as when associated with a HbS where the disease is mild sickle cell anemia as there is a residual activity of 20% HbA. The identification of such mutations is important for a good genetic counseling that will provide information to individuals and couples at risk (both carriers) in relation to the mode of inheritance, the genetic risk of having affected children and history nature of the disease, including treatment and thus make an informed decision about their reproductive options.
Session topic: E-poster
Keyword(s): Thalassemia
Abstract: PB2122
Type: Publication Only
Background
The β+-thalassemia is characterized by reduced production of beta chains, which can be produced by mutations in the promoter area (either the CACCC or TATA box). Depending on the extent of reduction of beta globin chain, the β+-thalassemia mutations may be classified into mild and silent. Silent β-thalassemia is characterized in the heterozygous state by normal MCV and MCH, normal or more frequently borderline HbA2, and normal HbF. Globin chain synthesis ratio is only slightly imbalanced, and sometimes even normal. This phenotype may escape detection by the usual methods, so DNA study being necessary for proper identification. Compound heterozygosity of these mutations with a severe mutation always produces very mild thalassemia intermedia. Frequently the diagnosis is made in adulthood or even in the elderly. Mild β-thalassemia mutations are characterized by a residual high β-chain production, show moderate thalassemia-like hematological features and imbalance chain synthesis. This group of molecular defects includes transcriptional mutants in the proximal CACCC box and in the TATA box. Homozygotes or compound hetrozygotes for these mild mutations usually have thalassemia intermedia.So far a total of 37 alterations have been described in the promoter region, some of which are ethnic specific, -87 C>T are common in Mediterranean areas, while -29 A>G and -88 C>T are frequently found in blacks.
Aims
In this report we present a compilation of the mutations found, in the promoter region of the β-globin gene, in only one Hospital in Madrid.
Methods
The hematological parameters were determined with Coulter LH750 Analyzer. HbA2 and HbF levels, as well as the different hemoglobins, were measured and analyzed by ion-exchange HPLC (VARIANTTM II). Hemoglobins were studied by capillary zone electrophoresis (CE) (Sebia). Genetic analysis of the β and Gγ globin genes was carried out by automatic sequencing and, in the case of α genes, by multiplex PCR.
Results
Conclusion
All these mutations show the importance of the promoter region in the β globin genes. Except for the mutation located at the distal CACCC (-101 C> T) that presents a β-thalassemia silent, the rest behaves as a β-thalassemia mild, generally high levels of HbA2 HbF and being the cause most likely the partial removal of competitiveness to limit transcription factors, facilitating their access to the promoters of both genes as the δ γ genes. Thus, as seen, any alteration in the CACCC proximal box and the TATA box, cause a moderate decline in the synthesis of the β globin chain, which has been tested both cases of thalassemia intermedia that they made their debut in the second decade of life with a moderate clinical as when associated with a HbS where the disease is mild sickle cell anemia as there is a residual activity of 20% HbA. The identification of such mutations is important for a good genetic counseling that will provide information to individuals and couples at risk (both carriers) in relation to the mode of inheritance, the genetic risk of having affected children and history nature of the disease, including treatment and thus make an informed decision about their reproductive options.
Session topic: E-poster
Keyword(s): Thalassemia
Type: Publication Only
Background
The β+-thalassemia is characterized by reduced production of beta chains, which can be produced by mutations in the promoter area (either the CACCC or TATA box). Depending on the extent of reduction of beta globin chain, the β+-thalassemia mutations may be classified into mild and silent. Silent β-thalassemia is characterized in the heterozygous state by normal MCV and MCH, normal or more frequently borderline HbA2, and normal HbF. Globin chain synthesis ratio is only slightly imbalanced, and sometimes even normal. This phenotype may escape detection by the usual methods, so DNA study being necessary for proper identification. Compound heterozygosity of these mutations with a severe mutation always produces very mild thalassemia intermedia. Frequently the diagnosis is made in adulthood or even in the elderly. Mild β-thalassemia mutations are characterized by a residual high β-chain production, show moderate thalassemia-like hematological features and imbalance chain synthesis. This group of molecular defects includes transcriptional mutants in the proximal CACCC box and in the TATA box. Homozygotes or compound hetrozygotes for these mild mutations usually have thalassemia intermedia.So far a total of 37 alterations have been described in the promoter region, some of which are ethnic specific, -87 C>T are common in Mediterranean areas, while -29 A>G and -88 C>T are frequently found in blacks.
Aims
In this report we present a compilation of the mutations found, in the promoter region of the β-globin gene, in only one Hospital in Madrid.
Methods
The hematological parameters were determined with Coulter LH750 Analyzer. HbA2 and HbF levels, as well as the different hemoglobins, were measured and analyzed by ion-exchange HPLC (VARIANTTM II). Hemoglobins were studied by capillary zone electrophoresis (CE) (Sebia). Genetic analysis of the β and Gγ globin genes was carried out by automatic sequencing and, in the case of α genes, by multiplex PCR.
Results
| Hb (g/dL) | VCM (fL) | HCM (pg) | HbA2-HbF (%) | OTHER MUTATION | SEX/AGE | ETHNIC | |
| -27 (A>T) β+ [I] | 13.9 | 80.4 | 26.6 | 4.2-0.5 | M/39 | C | |
| -28 (A>G) β+IIIIIIVVVI | 6.46.88.913.913.0 | 71.072.573.575.877.3 | 21.321.525.724.325.1 | 1.9-98.02.0-97.52.7-27.94.9-0.94.4-1.1 | CD71/72 (+A) β0CD71/72 (+A) β0CD41/42 (-TTCT) β0 | F/2F/2M/5F/29F/23 | ChChChChCh |
| -29 (A>G) β+VIIVIIIIXXXIXIIXIIIXIVXVXVIXVIIXVIIIXIXXXXXIXXIIXXIII | 12.612.810.111.712.314.26.812.115.210.912.814.19.512.56.96.812.8 | 74.272.373.573.375.878.383.268.972.762.567.174.388.578.062.061.273.4 | 25.322.623.323.524.626.126.021.323.718.219.823.526.725.227.028.925.7 | 5.1-5.55.3-3.86.9-3.36.5-4.15.0-3.97.0-4.05.7-10.34.2-6.33.8-5.04.3-0.44.0-0.84.6-1.73.0-17.05.0-3.56.0-9.58.0-30.05.2-3.4 | -α3.7/αα-α3.7/αα-α3.7/αα-α3.7/αα-α3.7/αα-α3.7/αα + [HbS]-α3.7/αα + [HbS] IVS-2-nt843 (T>G) β+IVS-1-nt5 (C>G) β++ -29 (A>G)-29 (A>G) | M/31F/28M/20 F/21M/42M/33F/22M/25M/17F/44M/53M/23F/24M/26M/25F/20 | BBBBBBBCBBBCCBBBB |
| -56 (G>C) β+ [XXIV] | 13.0 | 72 | 23.5 | 5.3-4.1 | M/23 | B | |
| -86 (C>A) β+XXVXXVIXXVII | 15.211.815.3 | 67.371.973.2 | 22.322.124.9 | 3.6-6.03.5-1.63.2-2.0 | M/77F/30M/32 | CCC | |
| -88 (C>T) β+XXVIIIXXIXXXXXXXIXXXIIXXXIIIXXXIV | 11.813.113.313.211.012.412.4 | 76.971.872.373.666.173.772.7 | 23.623.322.923.222.123.724.2 | 5.3-5.75.9-5.65.3-3.45.6-2.95.2-15.84.1-4.16.0-10.0 | [HbS][HbS][HbS] | F/25F/39F/50F/20F/4M/27F/27 | BCCCBBB |
| -101 (C>T) β+ [XXXIV] | 11.3 | 72.5 | 23.9 | 3.8-1.5 | M/2 | B |
Conclusion
All these mutations show the importance of the promoter region in the β globin genes. Except for the mutation located at the distal CACCC (-101 C> T) that presents a β-thalassemia silent, the rest behaves as a β-thalassemia mild, generally high levels of HbA2 HbF and being the cause most likely the partial removal of competitiveness to limit transcription factors, facilitating their access to the promoters of both genes as the δ γ genes. Thus, as seen, any alteration in the CACCC proximal box and the TATA box, cause a moderate decline in the synthesis of the β globin chain, which has been tested both cases of thalassemia intermedia that they made their debut in the second decade of life with a moderate clinical as when associated with a HbS where the disease is mild sickle cell anemia as there is a residual activity of 20% HbA. The identification of such mutations is important for a good genetic counseling that will provide information to individuals and couples at risk (both carriers) in relation to the mode of inheritance, the genetic risk of having affected children and history nature of the disease, including treatment and thus make an informed decision about their reproductive options.
Session topic: E-poster
Keyword(s): Thalassemia
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