Promoter mutations producing mild β‐thalassaemia in the Italian population

Meloni, Alessandra; Rosatelli, C; Faà, V.; Sardu, R; Saba, Luisella; Murru, S; Sciarratta, G. V.; Baldi, Maurizia; Tannoia, N; Vitucci, A.; Cao, Antonio

doi:10.1111/j.1365-2141.1992.tb08904.x

Cited by 28 publications

(6 citation statements)

References 1 publication

(1 reference statement)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Of particular interest is the rare β+ promotor mutation C-G at position -87 [28,29]. Interestingly, this mutation is present in the highest frequency, in Bulgaria where it has a frequency of 2, 6% [30].…”

Section: Discussionmentioning

confidence: 99%

Scanning of β‐globin gene for identification of β‐thalassemia mutation in Romanian population

Tălmaci

Traeger-Synodinos

Kanavakis

et al. 2004

J Cellular Molecular Medi

View full text Add to dashboard Cite

Abstractβ-Thalassemia is uncommon (0.5%) in the Romanian population, but it must be considered in the differential diagnosis of hypochromic anemia. The molecular characterization of β-thalassemia is absolutely necessary for molecular diagnosis, as well as any genetic epidemiological study in this region. Molecular analyses consist of mutation detection by molecular scanning of β-globin gene. This gene has 3 exons and 2 introns, involved in β-thalassemic pathogenesis. Clinical application of DNA analysis on β-thalassemic chromosomes allowed characterization of 29 persons with different β-thalassemia mutations among 58 patients with anemia. The experimental strategy was based on sequential PCR amplification of most of the β-globin gene and running on denaturing gradient gel electrophoresis of amplification products. Definitive characterization of mutations in samples identified with shifted DGGE patterns was performed ARMS-PCR and/or PCR-restriction enzyme analysis methods. Eight different β-thalassemia alleles were identified, the most common being IVS I-110 (G-A) and cd 39 (C-T). Comparison of overall frequency of mutations in the neighboring countries, shows that these results are in the frame of overall distribution of these mutations in Mediterranean area, especially in Greece and in Bulgaria. Molecular diagnosis is useful for differentiating mild from severe alleles, for genetic counseling, as well as for mutation definition in carriers, identified by hematological analysis necessary for prenatal testing and genetic counseling.

show abstract

Section: Discussionmentioning

confidence: 99%

Scanning of β‐globin gene for identification of β‐thalassemia mutation in Romanian population

Tălmaci

Traeger-Synodinos

Kanavakis

et al. 2004

J Cellular Molecular Medi

View full text Add to dashboard Cite

show abstract

“…It has been found that promoter mutations in factor IX (4,7,12,19,28,39,45,47,49), protein C (2), haptoglobin (16), and ␤-globin (10,31,(36)(37)(38) lead to disruption of the binding of transcription factors, with a resulting clinically significant reduction of gene expression. Such a lesion might be expected to affect the level of expression of the factor VIII protein and give rise to a clinical phenotype.…”

Section: Discussionmentioning

confidence: 99%

Role of the Liver-Enriched Transcription Factor Hepatocyte Nuclear Factor 1 in Transcriptional Regulation of the Factor VIII Gene

McGlynn

Mueller

Begbie

et al. 1996

Molecular and Cellular Biology

View full text Add to dashboard Cite

Coagulation factor VIII is an essential cofactor required for normal hemostatic function. A deficiency in factor VIII results in the bleeding disorder hemophilia A. Despite the fact that the factor VIII gene was cloned a decade ago, the mechanisms which control its transcription remain unresolved. In our studies, we have characterized 12 protein binding sites within the factor VIII promoter by DNase I protection assays performed with rat liver nuclear extracts. Three of these elements (sites 1 to 3) are situated within the 5 untranslated region of the gene, while three other sites (sites 4 to 6) lie within the first 100 bp upstream of the transcriptional start site. We have identified an additional site (site 7) ϳ300 bp upstream from site 6, as well as a cluster of five sites in a 250-bp region which terminates ϳ1 kb from the transcriptional start site. Seven of these binding sites (sites 2, 3, 4, 6, 7, 9, and 10) bind members of the C/EBP family of transcription factors. DBP also binds to five of these sites (sites 3, 4, 6, 7, and 9). Utilizing transient transfection studies in HepG2 cells, we have shown that deletion of the factor VIII promoter sequences distal to nucleotide ؊44 results in a significant but small increase in promoter activity. The activity of each of the various 5 deletion constructs is significantly enhanced by cotransfection of C/EBP␣ and D-site-binding protein expression plasmids, while cotransfection of both C/EBP␣ and C/EBP␤ plasmids resulted in a further enhancement of transactivation. These studies also provide evidence of a repressor element located between nucleotides ؊740 and ؊1002. Since the minimal promoter sequence (؊44 to ؉148) maintains the transcriptional activity of the full-length promoter sequence, we proceeded to identify additional factors binding to sites 1 to 4. Competition studies revealed that a ubiquitous transcription factor, NF-Y, binds to site 4, while the liver-enriched transcription factor hepatocyte nuclear factor I (HNF-1) binds to site 1. Mutation analysis of the minimal promoter demonstrated that HNF-1 is critical for activating transcription of the factor VIII gene in vitro. Our results also suggest that the multiple upstream elements that we have identified may act as a backup regulatory region in the event of disruption of the HNF-1 element in the 5 untranslated region.

show abstract

“…36/43 genotypes were each found only in one family. Based on previous reports and clinical observations, the b-thalassaemia alleles could be classified as very mild b þ alleles (also referred to as 'silent') in which there is minimal deficit of b-globin synthesis (Baklouti et al, 1986;Wong et al, 1987;Thein et al, 1988;Ristaldi et al, 1990;Olds et al, 1991;Ghanem et al, 1992;Meloni et al, 1992;Ho et al, 1996), mild b þ (Tamagnini et al, 1983;Chehab et al, 1987;Diaz-Chico et al, 1988;Wong et al, 1989;Yang et al, 1989) and severe b þ and bЊ (null) alleles (Table II). The distribution of these mutations were consistent with the different ethnic backgrounds and substantiate the molecular heterogeneity in this atypical group of b-thalassaemia patients.…”

Section: B-thalassaemia Genotypesmentioning

confidence: 99%

Beta‐thalassaemia intermedia: is it possible consistently to predict phenotype from genotype?

et al. 1998

View full text Add to dashboard Cite

Eighty-seven patients with beta thalassaemia of intermediate severity were investigated in our Unit to determine whether it is possible to consistently predict phenotypic severity from genotypic factors. The subjects were from the following ethnic backgrounds: Asian Indian (35.1%), Middle Eastern (24.3%), Mediterranean (21.6%), Northern European (14.9%) and South-East Asian/Chinese (4.1%). There was a wide spectrum of phenotypic severity; 49 had mild disease, 22 moderate and 16 severe disease. 22/87 patients had inherited only a single copy of a beta-thalassaemia allele, of whom 11 had also co-inherited triplicated alpha genes (alpha alpha alpha/alpha alpha or alpha alpha alpha/alpha alpha alpha) and seven had dominantly inherited beta thalassaemia. In four of the heterozygotes no explanation was found for the thalassaemia-intermedia phenotype. 65/87 patients were homozygous or compound heterozygous for 26 mutations (40 genotypes) which ranged from very mild beta+ to beta0 thalassaemia alleles. All patients with two mild or very mild beta+ thalassaemia alleles had mild to moderate disease. Although concurrent inheritance of extra alpha genes with heterozygous beta thalassaemia results in thalassaemia intermedia, the disease is mild. Co-inheritance of alpha thalassaemia as a modulating factor was not evident in this cohort of patients. Presence of the in-cis Xmn I-Ggamma site was a modulating factor but insufficient to explain the high fetal haemoglobin levels encountered. In conclusion, apart from the two categories of triplicated alpha genes with heterozygous beta thalassaemia and inheritance of mild beta+ thalassaemia alleles, it was not possible to consistently predict phenotype from alpha and beta genotypes alone, due to the influence of modulating factors, some implicated (such as inheritance of HPFH determinants) and others as yet unidentified.

show abstract

Promoter mutations producing mild β‐thalassaemia in the Italian population

Cited by 28 publications

References 1 publication

Scanning of β‐globin gene for identification of β‐thalassemia mutation in Romanian population

Scanning of β‐globin gene for identification of β‐thalassemia mutation in Romanian population

Role of the Liver-Enriched Transcription Factor Hepatocyte Nuclear Factor 1 in Transcriptional Regulation of the Factor VIII Gene

Beta‐thalassaemia intermedia: is it possible consistently to predict phenotype from genotype?

Contact Info

Product

Resources

About