Linkage of β-thalassaemia mutations and β-globin gene polymorphisms with DNA polymorphisms in human β-globin gene cluster

Orkin, Stuart H.; Kazazian, Haig H.; Antonarakis, Stylianos E.; Goff, Sabra C.; Boehm, Corinne D.; Sexton, Julianne P.; Waber, Pamela G.; Giardina, Patricia J.

doi:10.1038/296627a0

Cited by 902 publications

(387 citation statements)

References 31 publications

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“…In addition, a microsatellite, (AT) x (T) y , is subject to frequent micro-insertion or deletion [19]. We found (AT) 7 (T) 7 , (AT) 8 (T) 5 , and (AT) 9 (T) 5 configurations in the families studied here. No polymorphisms were observed in either the 5Ј or the 3Ј untranslated regions of the gene.…”

Section: Polymorphic Sites In ␤-Lcr Hs1 ␤-Lcr Hs2 ␤-Lcr Hs3 and ␤-mentioning

confidence: 68%

“…Nine single nucleotide polymorphisms and three length variants were identified in the ␤-globin gene cluster, and these sites could be segregated as eight sequence haplotypes in the thalassemia families studied. Three observed ␤-thalassemia mutations, codon 15 (G➝A), codon 30 (G➝C), and IVS1-5 (G➝C), were found to be linked with different sequence haplotype, and sequence variations within the structural gene refer to the framework as described by Orkin et al [5] (Table III). The codon 15 (G➝A) mutation is linked to haplotype A and sequence framework 4.…”

Section: Sequence Polymorphism Associated With ␤-Thalassemia Mutationsmentioning

confidence: 75%

“…Three length polymorphisms were observed in the (AT) x (T) y sequence region: (AT) 7 (T) 7 , (AT) 8 (T) 5 , and (AT) 9 (T) 5 . The AT dinucleotide insert accompanies either the presence or the absence of a T➝A replacement at −528, showing a +ATA,−T event as reported previously [23].…”

Section: Discussionmentioning

confidence: 99%

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Spectrum of β‐thalassemia mutations and their association with allelic sequence polymorphisms at the β‐globin gene cluster in an eastern Indian population

et al. 2002

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In this report, the spectrum of ␤-thalassemia mutations and genotype-to-phenotype correlations were defined in large number of patients (␤-thalassemia carriers and major) with varying disease severity in an Eastern Indian population mainly from the state of West Bengal. The five most common ␤-thalassemia mutations were detected, which included IVS1-5 (G➝C), codon 15 (G➝A), codon 26 (G➝A), codon 30 (G➝C), and codon 41/42 (−TCTT). These accounted for 85% in 80 ␤-thalassemic alleles deciphered from 56 patients, including ␤-thalassemia major and carriers, and 15% of alleles remained uncharacterized in these patients. Expression of the human ␤-globin gene is regulated by an array of cis-acting DNA elements, including five DNase I hypersensitive sites (HSs) in the locus control region (LCR), promoters that incorporate certain silencer elements, and enhancers at 3 of the ␤-globin gene. For detailed studies and to understand the molecular basis of ␤-thalassemia, we studied two groups of subjects: a group of 12 patients from four families having ␤-thalassemia major and carrier phenotype and a control group of 26 healthy individuals. In these two groups, we examined portions of the ␤-globin gene locus control region HSs 1, 2, 3, and 4, which included the (CA) x (TA) y repeat motif, the (AT) x N y (AT) z repeat motif, the inverted repeat sequence TGGGGACCCCA, the promoter region of the G ␥-globin gene, an (AT) x (T) y repeat 5 of the silencer region, and the ␤-globin gene and its 3 flanking region. We investigated the allelic sequence polymorphisms in these regions and their association with the ␤-thalassemia mutations to know the possible genotype-phenotype relationship in ␤-thalassemia patients. An analysis of cisacting regulatory regions showed varied sequence haplotypes associated with some frequent ␤-thalassemia mutations in this Eastern Indian population. Am.

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Section: Polymorphic Sites In ␤-Lcr Hs1 ␤-Lcr Hs2 ␤-Lcr Hs3 and ␤-mentioning

confidence: 68%

Section: Sequence Polymorphism Associated With ␤-Thalassemia Mutationsmentioning

confidence: 75%

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Spectrum of β‐thalassemia mutations and their association with allelic sequence polymorphisms at the β‐globin gene cluster in an eastern Indian population

et al. 2002

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“…The absence of a strong effect for a-thalassemia in SCD pulmonary hypertension was unexpected in contrast to the findings with Hb SC, despite the increased statistical power from the presence of the a 3.7 allele at nearly three times the frequency of Hb C. Still, the magnitude of a 3.7 's effect may be sufficiently small to be below the threshold for detection for the statistical power in this study. Likewise, haplotypes of the b-globin locus have been used in the past to study both the variation in SCD severity and the evolutionary history of the b S mutation [47][48][49][50]27]. In particular, some of the variability in Hb F expression is attributable to functional alleles in the fetal hemoglobin genes inherited on specific b S -globin haplotypes [48,[51][52][53].…”

Section: Discussionmentioning

confidence: 99%

Mutations and polymorphisms in hemoglobin genes and the risk of pulmonary hypertension and death in sickle cell disease

et al. 2007

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Pulmonary hypertension is a common complication of sickle cell disease (SCD) and a risk factor for early death. Hemolysis may participate in its pathogenesis by limiting nitric oxide (NO) bioavailability and producing vasculopathy. We hypothesized that hemoglobin mutations that diminish hemolysis in SCD would influence pulmonary hypertension susceptibility. Surprisingly, coincident a-thalassemia (Odds Ratio [OR] 5 0.95, 95% CI 5 0.46-1.94, P 5 NS) was not associated with pulmonary hypertension susceptibility in homozygous SCD. However, pulmonary hypertension cases were less likely to have hemoglobin SC (OR 5 0.18, 95% confidence interval [CI] 5 0.06-0.51, P 5 0.0005) or Sb 1 thalassemia (OR 5 0.25, 95% CI 5 0.06-1.16, P 5 0.10). These compound heterozygotes may be protected from pulmonary hypertension because of reduced levels of intravascular hemolysis, but develop this complication at a lower rate possibly due to the presence of non-hemolytic risk factors such as renal dysfunction, iron overload and advancing age. Despite this protective association, patients with SC who did develop pulmonary hypertension remained at significant risk for death during 49 months of followup (Hazard Ratio 5 8.20, P 5 0.0057). Am.

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“…Using 7 RFLP sites, at least nine RFLP haplotypes-named I to IXhave been found in the Mediterranean area [20].…”

Section: Introductionmentioning

confidence: 99%

?-globin gene cluster haplotypes associated with ?-thalassemia on Corsica island

Falchi¹,

Giovannoni²,

Vacca³

et al. 2004

Am. J. Hematol.

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In the Corsican population, the incidence of b-thalassemia traits is reported to be 3.1%. We have investigated the 2 more important b-thalassemia mutations present in the Corsican population: b 0 -39 and b + IVS1-110. Seven polymorphic sites in the b-globin gene cluster were analyzed from a sample of 43 non-related b-thalassemia heterozygotes and of 47 nonrelated healthy individuals, from Central Corsica (Corte). Among the 43 Corsican patients analyzed, the nonsense codon is predominant (88.40%), whereas the b + IVS1-110 mutation, the most common of b-thalassemia in the eastern part of the Mediterranean basin, is underrepresented (2.33%). The other individuals did not show positive for the two tested mutations (9.27%). The b 0 -39 mutation in the studied population shows a strong association with haplotype II (18.7%) and a weaker association with haplotypes I (2.3%) and VII (2.1%). The strong association of the b 0 -39 mutation with haplotype II was also found in Sardinia, suggesting that the mutation on the two islands have the same origin. In the present study all the data concerning frequencies of the mutations and of sequence haplotypes, support the hypothesis of a western Mediterranean origin of the b 0 -39 mutation. For the first time, this paper analyzes the association of b-globin gene cluster haplotypes with the 2 more frequent b-thalassemia mutations in an isolated population in the centre of Corsica (Corte), which presents certain genetic peculiarities. However, the analysis of b-haplotypes will be very useful for the genetic epidemiological study in this region. Am.

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Linkage of β-thalassaemia mutations and β-globin gene polymorphisms with DNA polymorphisms in human β-globin gene cluster

Cited by 902 publications

References 31 publications

Spectrum of β‐thalassemia mutations and their association with allelic sequence polymorphisms at the β‐globin gene cluster in an eastern Indian population

Spectrum of β‐thalassemia mutations and their association with allelic sequence polymorphisms at the β‐globin gene cluster in an eastern Indian population

Mutations and polymorphisms in hemoglobin genes and the risk of pulmonary hypertension and death in sickle cell disease

?-globin gene cluster haplotypes associated with ?-thalassemia on Corsica island

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