Identification and molecular characterization of four new large deletions in the β-globin gene cluster

Joly, Philippe; Lacan, Philippe; Garcia, Cyrielle; Couprie, Nicole; Francina, Alain

doi:10.1016/j.bcmd.2009.01.017

Cited by 24 publications

(14 citation statements)

References 30 publications

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“…They carry recently described deletions removing the the 5' d-globin BCL11A binding domain (Figure 1): the French WestIndies deletion or the Algerian deletion. 10 The average HbF level found in these patients was 4.16 g/dL (SD 0.96, n=3) and the highest values of HbF (5.24 and 4.10 g/dL) previously reported for these deletions 11 is in agreement with our findings.…”

Section: Resultssupporting

confidence: 92%

Estimation of the difference in HbF expression due to loss of the 5' -globin BCL11A binding region

Ghedira

Lecerf²,

Faubert³

et al. 2012

Haematologica

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ARTICLES 305 Thalassemia Syndromes IntroductionA growing number of studies describe BCL11A as a major repressor of fetal hemoglobin (HbF) expression. These include the description of several single nucleotide polymorphisms (SNPs) located in the BCL11A gene and linked to HbF level, and thus, the severity of sickle cell disease and beta-thalassemia (bthal) 1-4 and the demonstration of the direct binding of this transcription factor onto several locations in the b-globin cluster, in particular, to a region located 5' to the d-globin gene. 5 All these studies allow us to draw a network of co-operating transacting factors (KLF1, SOX6, GATA1 and BCL11A) involved in the switch between fetal and adult hemoglobin (Hb). A recent study 6 using the analysis of large deletions has defined a critical area located 5' to the d-globin gene that appears to exert the main repressor activity of BCL11A.However, if the role of the BCL11A binding region is now well documented, no studies have evaluated the consequence of the deletion of that region in terms of HbF output. We report the precise analysis of the correlation between phenotype and genotype of patients displaying a short deletion (under 25 kb) differing at the 5' d-globin gene breakpoint. The short length of the deletions found in our patients makes these events not comparable with hereditary persistence of fetal Hb (HPFH) deletions whose mechanism is likely to bring the 3'HS (3' hypersensitive site) activator site close to the g-globin genes, and thus enhances HbF expression. Design and MethodsA cohort of 10 patients was selected from our DNA bank of patients referred to our laboratory for the molecular analysis of a bthal phenotype. Prior to sampling, patients received genetic counseling and gave their written, informed consent to the study. The selected patients were heterozygous carriers of a short deletion featuring the 5' breakpoint within the gb-d intergenic region. The phenotypic analysis of patients included red blood cell (RBC) count carried out on an automated cell counter, and Hb study using cation exchange high performance liquid chromatography (HPLC) (VARI-ANT II™; Bio-Rad Laboratories, Hercules, CA, USA). 8 The results are shown in Table 1. Relevant hematologic data were obtained to verify that no patient had received a blood transfusion which could compromise data interpretation. This retrospective study was approved by the Institutional Review Board of the Henri Mondor Hospital, Créteil, France.The molecular analysis of the b-globin cluster was achieved including deletion detection using the quantitative multiplex polymerase chain reaction of short fragment (QMPSF) procedure. 9Precise localization of unknown breakpoints was determined using a custom CGH-array chip with high probe density on the b-and aglobin clusters, 10 and achieved by amplification then sequencing, using primers extrapolated from probes flanking the deletions (Online Supplementary Figures S1-S6).In order to evaluate any correlation as precisely as possible, genotyping of the a-globin c...

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Section: Resultssupporting

confidence: 92%

Estimation of the difference in HbF expression due to loss of the 5' -globin BCL11A binding region

Ghedira

Lecerf²,

Faubert³

et al. 2012

Haematologica

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“…In fact, it has been more than 10 years ago since studies showed this region's critical role in γto β-globin expression switching (27)(28)(29). Lately, Sankaran et al (21) were able to demonstrate the role of a 3.5 kb intergenic region, upstream of the HBD gene, in fetal globin silencing, via the binding of the BCL11A repressor and its binding partner HDAC1.…”

Section: Discussionmentioning

confidence: 95%

A Single Nucleotide Polymorphism in theHBBP1Gene in the Human β-Globin Locus is Associated with a Mild β-Thalassemia Disease Phenotype

et al. 2012

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The rs2071348 (g.5264146A>C) polymorphism on the HBB pseudogene, namely HBBP1, previously emerged as a variant significantly associated with a milder disease phenotype in Asian β(0)-thalassemia/hemoglobin (Hb) E (β(0)-thal/Hb E [β26(B8)Glu→Lys, GAG>AAG]) patients. In this study, we aimed to explore the possible association of rs2071348 with β-thalassemia (β-thal) disease severity in a group of β-thal major (β-TM) patients (severe phenotype) and β-thal intermedia (β-TI) patients (mild phenotype) of Hellenic origin and compare the results with normal (non thalassemic) individuals of the same origin. In addition, we explored whether this single nucleotide polymorphism (SNP) can be exploited as a pharmacogenomic marker to predict the outcome of Hb F-augmenting therapy in β-thal patients receiving hydroxyurea (HU). Our data suggest that the rs2071348 polymorphism is associated with higher Hb F levels and a milder β-thal disease phenotype. However, the rs2071348 polymorphism in the HBBP1 gene does not correlate with response to HU treatment.

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“…The heights of different specific probes were compared with those of reference probes. A serial of semi-quantitative multiplex PCRs was performed to pinpoint the new deletion as previously described (12). Finally, the breakpoints of the new deletion were defined by a long range gap-PCR and DNA sequencing.…”

Section: Methodsmentioning

confidence: 99%

A Novel Deletion/Insertion Caused by a Replication Error in the β-Globin Gene Locus Control Region

et al. 2011

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Deletions in the β-globin locus control region (β-LCR) lead to (εγδβ)(0)-thalassemia [(εγδβ)(0)-thal]. In patients suffering from these rare deletions, a normal hemoglobin (Hb), phenotype is found, contrasting with a hematological thalassemic phenotype. Multiplex-ligation probe amplification (MLPA) is an efficient tool to detect β-LCR deletions combined with long-range polymerase chain reaction (PCR) and DNA sequencing to pinpoint deletion breakpoints. We present here a novel 11,155 bp β-LCR deletion found in a French Caucasian patient which removes DNase I hypersensitive site 2 (HS2) to HS4 of the β-LCR. Interestingly, a 197 bp insertion of two inverted sequences issued from the HS2-HS3 inter-region is present and suggests a complex rearrangement during replication. Carriers of this type of thalassemia can be misdiagnosed as an α-thal trait. Consequently, a complete α- and β-globin gene cluster analysis is required to prevent a potentially damaging misdiagnosis in genetic counselling.

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Identification and molecular characterization of four new large deletions in the β-globin gene cluster

Cited by 24 publications

References 30 publications

Estimation of the difference in HbF expression due to loss of the 5' -globin BCL11A binding region

Estimation of the difference in HbF expression due to loss of the 5' -globin BCL11A binding region

A Single Nucleotide Polymorphism in theHBBP1Gene in the Human β-Globin Locus is Associated with a Mild β-Thalassemia Disease Phenotype

A Novel Deletion/Insertion Caused by a Replication Error in the β-Globin Gene Locus Control Region

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