Genotype–phenotype correlation and report of novel mutations in β-globin gene in thalassemia patients

Nagar, Rachana; Sinha, Sujata; Raman, Rajiva

doi:10.1016/j.bcmd.2015.03.005

Cited by 13 publications

(8 citation statements)

References 18 publications

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“…Patients who are homozygous or double heterozygotes for mutations in the β‐globin gene that lead to mild or moderate decrease in β‐globin production have β‐thalassemia intermedia (β‐TI), and display varying degrees of anemia, requiring occasional transfusions. β‐TI covers the spectrum between heterozygous β‐thalassemia and β‐TM .…”

Section: Introductionmentioning

confidence: 99%

2017 Clinical trials update in new treatments of β‐thalassemia

et al. 2016

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The underlying basis of b-thalassemia pathology is the diminished b-globin synthesis leading to a-globin accumulation and premature apoptotic destruction of erythroblasts, causing oxidative stress-induced ineffective erythropoiesis, bone marrow hyperplasia, splenomegaly, and increased intestinal iron absorption with progressive iron overload. Better understanding of the molecular mechanisms underlying this disease led to the recognition of new targets with potential therapeutic utility. Agents such as JAK2 inhibitors and TGF-b ligand traps that reduce the ineffective erythropoiesis process are already being tested in clinical trials with promising results. Other agents that aim to reduce oxidative stress (activators of Foxo3, HRIeIF2aP, Prx2, Hsp70, and PK anti-oxidant systems and inhibitors of HO-1) and to decrease iron overload (hepcidin agonists, erythroferrone inhibitors and exogenous transferrin) are also under experimental investigation. Significant progress has also been made in the area of allogeneic hematopoietic stem cell transplantation with several ongoing clinical trials examining new condition regimens as well as different donor selection and stem cell source options. Gene therapy has reached a critical point and phase 1 clinical trials have recently been launched to examine the effectiveness and especially long term safety. Epigenetic manipulation and genomic editing of the g-or b-globin gene are novel and promising experimental gene therapy approaches for b-thalassemia giving hope for cure for this chronic disease. This review outlines the key points of the molecular mechanisms underlying b-thalassemia in relation to the development of new therapies and an update is given both at the pre-clinical and clinical level.

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Section: Introductionmentioning

confidence: 99%

2017 Clinical trials update in new treatments of β‐thalassemia

et al. 2016

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“…There are a few recent reports of novel mutations as well like Codon 2 (−A), −42 (C>G), and −223 (T>C) from eastern India and Codon 53 (C>T) from West Bengal . We identified 49 different mutations which also included some novel and very rare ones.…”

Section: Discussionmentioning

confidence: 90%

“…[32][33][34] A meta-analysis on 17 selected studies comprising 8505 alleles nationally showed that 52 mutations represented 97.5% of all the β thalassemia alleles with IVS I-5 (G>C) varying from 44.8% in the north to 71.4% in the east. 33 There are a few recent reports of novel mutations as well like Codon 2 (−A), −42 (C>G), and −223 (T>C) from eastern India 35 and Codon 53 (C>T) from West Bengal. 36 We identified 49 different mutations which also included some novel and very rare ones.…”

Section: Discussionmentioning

confidence: 99%

The phenotypic and molecular diversity of hemoglobinopathies in India: A review of 15 years at a referral center

Nadkarni

Gorakshakar

Sawant

et al. 2018

Int J Lab Hematology

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Introduction The hemoglobinopathies pose a significant health burden in India. Apart from the β thalassemias and sickle cell disorders, α thalassemias and structural hemoglobin variants are also common. Here we have reviewed the phenotypic and molecular diversity of hemoglobinopathies encountered at a referral center in western India over a period of 15 years. Materials and Methods Screening for hemoglobinopathies was done using HPLC and cellulose acetate electrophoresis. Molecular characterization was done using Covalent Reverse Dot Blot Hybridization (CRDB), Amplification Refractory Mutation System (ARMS), GAP PCR and direct DNA sequencing. Results The study includes 31 075 individuals who were referred for diagnosis of hemoglobinopathies and prenatal diagnosis. Of these 14 423 individuals showed various hemoglobin abnormalities. Beta genotyping in 5615 individuals showed the presence of 49 β thalassemia mutations. 143 β thalassemia heterozygotes had normal or borderline HbA2 levels. We identified three δ gene mutations (HbA2 Pellendri, HbA2 St.George, HbA2 Saurashtra) in β thalassemia heterozygotes leading to normal HbA2 levels. The commonest defects among the raised Hb F determinants were Gγ(Αγδβ)0 Indian inversion and the HPFH‐3 Indian deletion. A total of 312 individuals showed the presence of α thalassemia, of which 12.0% had a single α gene deletion (−α/αα). HbH disease was identified in 29 cases with 10 different genotypes. Alpha globin gene triplication was seen in 2.1% of β thalassemia heterozygotes with a thalassemia intermedia phenotype. Seven unusual α chain variants and eight uncommon β chain variants were identified. Conclusion The repertoire of molecular defects seen in the different globin genes will be valuable for management and control of these disorders both in India as well as in other countries where there is a huge influx of migrant populations from India.

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“…Hematological parameters in the family with a frameshift mutation at Codon 4 (-C) in the β-globin gene. deletion variants described in codons 1, 2, 5, and 6 of the β-globin gene are responsible for β 0 -thalassemic alleles [22][23][24][25].…”

Section: Discussionmentioning

confidence: 99%