Novel large deletions in the human α-globin gene cluster: Clarifying the HS-40 long-range regulatory role in the native chromosome environment

Coelho, Andreia; Picanço, Isabel; Seuanes, Filomena; Seixas, Maria Teresa; Faustino, Paula

doi:10.1016/j.bcmd.2010.05.010

Cited by 46 publications

(41 citation statements)

References 21 publications

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“…1) (Phylipsen et al 2010). The phenotype (HbH disease) of the proband, which carries the same small deletion on both copies of chromosome 16, is consistent with expression of both cis-linked a genes being down-regulated but not completely abolished (Coelho et al 2010). This suggests that other cis-acting elements on this chromosome ( possibly MCS-R1) can activate a-globin expression.…”

Section: Deletions Removing the Upstream Regulatory Elements Of The Amentioning

confidence: 69%

The Molecular Basis of -Thalassemia

Higgs

2013

Cold Spring Harbor Perspectives in Medicine

119

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The globin gene disorders including the thalassemias are among the most common human genetic diseases with more than 300,000 severely affected individuals born throughout the world every year. Because of the easy accessibility of purified, highly specialized, mature erythroid cells from peripheral blood, the hemoglobinopathies were among the first tractable human molecular diseases. From the 1970s onward, the analysis of the large repertoire of mutations underlying these conditions has elucidated many of the principles by which mutations occur and cause human genetic diseases. This work will summarize our current knowledge of the a-thalassemias, illustrating how detailed analysis of this group of diseases has contributed to our understanding of the general molecular mechanisms underlying many orphan and common diseases.

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Section: Deletions Removing the Upstream Regulatory Elements Of The Amentioning

confidence: 69%

The Molecular Basis of -Thalassemia

Higgs

2013

Cold Spring Harbor Perspectives in Medicine

119

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“…In a rare naturally occurring deletion removing only the MCS-R2 region, individuals with a heterozygous mutation have a reduced a-globin chain output similar to that seen in mild a-thalassemia, which is desirable to produce a beneficial effect in b-thalassemia. 93 A rare homozygote for this deletion has HbH disease, but importantly, no other abnormality, showing that this element can be removed with no other untoward effects. 93 Therefore, disruption of this single element using programmable nucleases has the potential to be a very useful and simple therapeutic strategy in patients with b-thalassemia, and in particular for those with the common HbE b-thalassemia genotype.…”

Section: 88mentioning

confidence: 99%

“…93 A rare homozygote for this deletion has HbH disease, but importantly, no other abnormality, showing that this element can be removed with no other untoward effects. 93 Therefore, disruption of this single element using programmable nucleases has the potential to be a very useful and simple therapeutic strategy in patients with b-thalassemia, and in particular for those with the common HbE b-thalassemia genotype.…”

Section: 88mentioning

confidence: 99%

α-Globin as a molecular target in the treatment of β-thalassemia

Mettananda

Gibbons

Higgs

2015

Blood

122

120

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The thalassemias, together with sickle cell anemia and its variants, are the world’s most common form of inherited anemia, and in economically undeveloped countries, they still account for tens of thousands of premature deaths every year. In developed countries, treatment of thalassemia is also still far from ideal, requiring lifelong transfusion or allogeneic bone marrow transplantation. Clinical and molecular genetic studies over the course of the last 50 years have demonstrated how coinheritance of modifier genes, which alter the balance of α-like and β-like globin gene expression, may transform severe, transfusion-dependent thalassemia into relatively mild forms of anemia. Most attention has been paid to pathways that increase γ-globin expression, and hence the production of fetal hemoglobin. Here we review the evidence that reduction of α-globin expression may provide an equally plausible approach to ameliorating clinically severe forms of β-thalassemia, and in particular, the very common subgroup of patients with hemoglobin E β-thalassemia that makes up approximately half of all patients born each year with severe β-thalassemia.

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“…Since then, multiple investigators have used MLPA to assess for a variety of deletions and mutations within the ␣-globin gene cluster and flanking genes. [11][12][13][14][15] A majority of these publications use MLPA primarily as a tool for detecting and classifying novel deletions that remain uncharacterized by prior testing methods such as SB, sequence analysis, and gap- ) was correct (SB result was misinterpreted).…”

Section: Discussionmentioning

confidence: 99%

Development and Clinical Implementation of a Combination Deletion PCR and Multiplex Ligation-Dependent Probe Amplification Assay for Detecting Deletions Involving the Human α-Globin Gene Cluster

Kipp

Roellinger

Lundquist

et al. 2011

The Journal of Molecular Diagnostics

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The ␣-thalassemias are a group of hereditary disorders caused by reduced synthesis of the ␣-chain of hemoglobin. We have developed and tested an ␣-thalassemia assay that uses both multiplex ligationdependent probe amplification (MLPA) with Luminex-based detection and deletion PCR technologies. The MLPA assay consisted of 20 probes, 15 of which hybridized to the ␣-globin gene cluster and 5 that served as control probes. A PCR assay was developed to confirm the presence of heterozygous/homozygous 3.7-kb and 4.2-kb deletions. MLPA and PCR results were compared to Southern blot (SB) results from 758 and 133 specimens, respectively. Lastly, MLPA and PCR results were reviewed and summarized from 5386 clinically tested specimens. SB and MLPA results were concordant in 678/687 (99%) specimens. PCR detected all deletions detected by SB with no false positives. No deletions or duplications were identified in 2630 (49%) clinically tested specimens. Extra ␣-globin copies were identified in 76 patients. A deletion of one or two ␣-globin genes was identified in 1251 (23%) and 1349 (25%) specimens, respectively, including 15 different genotypes. A deletion of three (hemoglobin H) and four ␣-globin genes (Hb Bart's) was observed in 65 or 3 specimens, respectively. Six patients had a deletion within the ␣-globin regulatory region MCS-R2. Thus, MLPA plus deletion PCR identify multiple ␣-globin gene deletions/duplications in patients being tested for ␣-thalassemia. The ␣-thalassemias are a group of recessively inherited disorders caused by reduced or absent synthesis of the ␣-chain of hemoglobin (Hb). Approximately 5% of the world's population is thought to be affected by ␣-thalassemia, making it one of the most common genetic disorders.1 Because of its selective advantage, the carrier rate of ␣-thalassemia is extremely high (Ͼ90%) in tropical and subtropical regions with a history of endemic malaria. 2The phenotype of patients with ␣-thalassemia is variable depending on the number of dysfunctional or absent ␣-globin genes. Patients with one dysfunctional ␣-globin gene (silent carrier) are often asymptomatic and unaware they have the genetic disorder unless they have a complete blood count examined. Similarly, patients with a deletion of two of the four ␣-globin genes (␣-thalassemia trait) may be asymptomatic and require no specific treatment. Hemoglobin H (three ␣-globin genes deleted/dysfunctional) is often more serious and is characterized by microcytic hypochromic hemolytic anemia, splenomegaly, and jaundice. All four of the ␣-globin alleles are dysfunctional in patients with Hb Bart's, the most severe and often fatal form of ␣-thalassemia. 2,3The two genes responsible for synthesis of the ␣-chain of Hb, HBA1 and HBA2, are located in the telomeric region on chromosome 16 (16p13.3) and encode ␣ 1 -globin and ␣ 2 -globin, respectively.2 These two genes are embedded within two highly homologous 4-kb duplication units that can be subdivided into separate homology blocks, written X, Y, and Z.2 Misalignment and recombination within ...

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Novel large deletions in the human α-globin gene cluster: Clarifying the HS-40 long-range regulatory role in the native chromosome environment

Cited by 46 publications

References 21 publications

The Molecular Basis of -Thalassemia

The Molecular Basis of -Thalassemia

α-Globin as a molecular target in the treatment of β-thalassemia

Development and Clinical Implementation of a Combination Deletion PCR and Multiplex Ligation-Dependent Probe Amplification Assay for Detecting Deletions Involving the Human α-Globin Gene Cluster

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