scholarly journals Evidence of new intragenic HBB haplotypes model for the prediction of beta-thalassemia in the Malaysian population

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nur-Aisyah Aziz ◽  
Wan-Rohani Wan Taib ◽  
Nur-Khairunnisa Kharolazaman ◽  
Imilia Ismail ◽  
Hamid Ali Nagi Al-Jamal ◽  
...  
Keyword(s):  
Association Analysis ◽  
Globin Gene ◽  
Beta Thalassemia ◽  
Beta Globin ◽  
Haplotype Association ◽  
Malaysian Population ◽  
Archived Samples ◽  
Potential Use ◽  
Online Software

AbstractThis study sought to determine the potential role of HBB haplotypes to predict beta-thalassemia in the Malaysian population. A total of 543 archived samples were selected for this study. Five tagging SNPs in the beta-globin gene (HBB; NG_000007.3) were analyzed for SNP-based and haplotype association using SHEsis online software. Single-SNP-based association analysis showed three SNPs have a statistically significant association with beta-thalassemia. When Bonferroni correction was applied, four SNPs were found statistically significant with beta-thalassemia; IVS2-74T>G (padj = 0.047), IVS2-16G>C (padj = 0.017), IVS2-666C>T (padj = 0.017) and 3’UTR + 314G>A (padj = 0.002). However, 3'UTR + 233G>C did not yield a significant association with padj value = 0.076. Further investigation using combined five SNPs for haplotype association analysis revealed three susceptible haplotypes with significant p values of which, haplotypes 1-2-2-1-1 (p = 6.49 × 10−7, OR = 10.371 [3.345–32.148]), 1-2-1-1-1 (p = 0.009, OR = 1.423 [1.095–1.850] and 1-1-1-1-1 (p = 1.39 × 10−4, OR = 10.221 [2.345–44.555]). Three haplotypes showed protective effect with significant p value of which, 2-2-1-1-1 (p = 0.006, OR = 0.668 [0.500–0.893]), 1-1-2-2-1 (p = 0.013, OR = 0.357 [0.153–0.830]) and 1-1-2-1-1 (p = 0.033, OR = 0.745 [0.567–0.977]). This study has identified the potential use of intragenic polymorphic markers in the HBB gene, which were significantly associated with beta-thalassemia. Combining these five SNPs defined a new haplotype model for beta-thalassemia and further evaluation for predicting severity in beta-thalassemia.

scholarly journals Evidence of New Intragenic HBB Haplotypes Model for the Prediction of Beta-Thalassemia in the Malaysian Population

2021 ◽  
Author(s):  
Nur-Aisyah Aziz ◽  
Wan-Rohani Wan Taib ◽  
Nur-Khairunnisa Kharolazaman ◽  
Imilia Ismail ◽  
Hamid Ali Nagi Al-Jamal ◽  
...  
Keyword(s):  
Association Analysis ◽  
Globin Gene ◽  
Beta Thalassemia ◽  
P Value ◽  
Beta Globin ◽  
Haplotype Association ◽  
Malaysian Population ◽  
Archived Samples ◽  
Protective Haplotype

Abstract This study sought to determine the potential role of HBB haplotypes for the prediction of beta-thalassemia in the Malaysian population. A total of 543 archived samples were reviewed and selected for this study. Five tagging SNPs in the beta-globin gene (HBB; NG_000007.3) were recorded and analysed for SNP-based and haplotype association using SHEsis online software. Single-SNP-based association analysis showed three tagging SNPs have statistical significant association with beta-thalassemia; IVS2-16G>C (p=0.036), IVS2-666C>T (p=0.032) and 3’UTR +314G>A (p=0.004). However, two tagging SNPs assigned as IVS2-74T>G and 3’UTR +233G>C did not yield significant association with p-value 0.099 and 0.211, respectively. In a further investigation, combined five tagging SNPs for haplotype association analysis revealed three susceptible haplotypes with significant p-values of which, assigned as haplotypes 1-2-2-1-1 (p=6.49x10-7, OR=10.371 [3.345~32.148]), 1-2-1-1-1 (p= 0.009, OR=1.423 [1.095~1.850] and 1-1-1-1-1 (p=1.39x10-4, OR=10.221 [2.345~44.555]). Another three haplotypes were found to be protective haplotype with significant p-value of which assigned as haplotypes 2-2-1-1-1 (p=0.006, OR=0.668 [0.500~0.893]), 1-1-2-2-1 (p=0.013, OR=0.357 [0.153~0.830]) and 1-1-2-1-1 (p=0.033, OR=0.745 [0.567~0.977]). This study has identified the potential use of intragenic polymorphic markers in the HBB gene, which were significantly associated with beta-thalassemia. A combination of these five tagging SNPs defined a new haplotype model for beta-thalassemia and further evaluation for the prediction of severity in beta-thalassemia.

scholarly journals beta-thalassemia intermedia in a Brazilian patient with - 101(C > T) and codon 39 (C > T) mutations

2003 ◽  
Vol 121 (1) ◽  
pp. 28-30
Author(s):  
Sylvia Morais de Sousa ◽  
Letícia Khater ◽  
Luís Antônio Peroni ◽  
Karine Miranda ◽  
Marcelo Jun Murai ◽  
...  
Keyword(s):  
Clinical Course ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Hypochromic Anemia ◽  
Beta Thalassemia ◽  
Beta Globin ◽  
Thalassemia Intermedia ◽  
Mean Cell Volume ◽  
Molecular Alterations ◽  
Brazilian Patient

CONTEXT: We verified molecular alterations in a 72-year-old Brazilian male patient with a clinical course of homozygous beta-thalassemia intermedia, who had undergone splenectomy and was surviving without regular blood transfusions. The blood cell count revealed microcytic and hypochromic anemia (hemoglobin = 6.5 g/dl, mean cell volume = 74 fl, mean cell hemoglobin = 24 pg) and hemoglobin electrophoresis showed fetal hemoglobin = 1.3%, hemoglobin A2 = 6.78% and hemoglobin A = 79.4%. OBJECTIVE: To identify mutations in a patient with the symptoms of beta-thalassemia intermedia. DESIGN: Molecular inquiry into the mutations possibly responsible for the clinical picture described. SETTING: The structural molecular biology and genetic engineering center of the Universidade Estadual de Campinas, Campinas, Brazil. PROCEDURES: DNA extraction was performed on the patient's blood samples. The polymerase chain reaction (PCR) was done using five specific primers that amplified exons and the promoter region of the beta globin gene. The samples were sequenced and then analyzed via computer programs. RESULTS: Two mutations that cause the disease were found: -101 (C > T) and codon 39 (C > T). CONCLUSIONS: This case represents the first description of 101 (C > T) mutation in a Brazilian population and it is associated with a benign clinical course.

scholarly journals The inactive beta globin gene on a gamma delta beta thalassemia chromosome has a normal structure and functions normally in vitro

Blood ◽  
1988 ◽  
Vol 71 (3) ◽  
pp. 766-770
Author(s):  
PT Curtin ◽  
YW Kan
Keyword(s):  
Globin Gene ◽  
Large Deletion ◽  
Beta Thalassemia ◽  
Ribonuclease Protection Assay ◽  
Beta Globin ◽  
Gamma Delta ◽  
Beta Globin Gene ◽  
Thalassemia Minor

We have previously described an English family with gamma delta beta- thalassemia in which a large deletion stops 25 kilobases (kb) upstream from the beta-globin gene locus, and yet the beta-globin gene is inactive in vivo. Affected family members had a beta-thalassemia minor phenotype with a normal hemoglobin A2 level. Gene mapping showed that these subjects were heterozygous for a chromosome bearing a large deletion that began in the G gamma-globin gene, extended through the epsilon-globin gene, and continued upstream for at least 75 kb. The A gamma-, delta-, and beta-globin gene loci on this chromosome were intact. To examine the possibility that an additional defect was present in the beta-globin gene, we cloned, sequenced, and examined the expression of the beta-globin gene from the affected chromosome. No mutation was found in the beta-globin gene sequence from 990 base-pairs 5′ to the cap site to 350 basepairs 3′ to the polyadenylation signal. The gene was subcloned into an expression vector and introduced into HeLa cells. Analysis of RNA derived from these cells, using a ribonuclease protection assay, revealed qualitatively and quantitatively normal transcription. Thus a structurally and functionally normal beta-globin gene is inactive in the presence of a large deletion more than 25 kb upstream. The loss of beta-globin gene function may be due to disturbance of chromatin conformation caused by the deletion or may be the result of loss of upstream sequences that are necessary for beta-globin gene expression in vivo.

scholarly journals Molecular analysis of Japanese delta beta-thalassemia

Blood ◽  
1988 ◽  
Vol 72 (5) ◽  
pp. 1771-1776
Author(s):  
S Shiokawa ◽  
H Yamada ◽  
Y Takihara ◽  
E Matsunaga ◽  
Y Ohba ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Beta Thalassemia ◽  
Globin Genes ◽  
Beta Globin ◽  
Beta Globin Gene ◽  
Gamma Globin ◽  
Large Deletions ◽  
Deletion Junction

A DNA fragment containing the deletion junction region from a Japanese individual with homozygous delta beta-thalassemia has been cloned. A clone containing the normal DNA surrounding the 3′ breakpoint of this deletion and a clone carrying the G gamma- and A gamma-globin genes of this patient were also isolated. Sequences of the deletion junction and both gamma-globin genes were determined. A comparison of these sequences with previously determined sequences of the normal counterparts revealed that the 5′ breakpoint is located between 2,134 and 2,137 base pairs (bp) 3′ to the polyA site of the A gamma-globin gene, the 5′ breakpoint is located just downstream of the 3′ border of the fetal gamma-globin duplication unit, and no molecular defects are evident within the gamma-globin gene region. A comparison between the sequences of the normal DNA surrounding the 3′ breakpoint and the normal DNA surrounding the 5′ breakpoint shows that deletion is the result of a nonhomologous recombination event. There are A+T-rich stretches near the 5′ and 3′ breakpoints in the normal DNA, and a portion of an Aly repeat is located in the region 3′ to the 3′ breakpoint. Southern blot analysis using probes 3′ to the beta-globin gene showed that the deletion extends in the 3′ direction further than any other deletions associated with delta beta-thalassemia and hereditary persistence of fetal hemoglobin (HPFH) heretofore reported. These results are discussed in terms of the mechanism generating large deletions in mammalian cells and three models for the regulation of gamma-globin and beta-globin gene expression in humans.

scholarly journals Current Perspective of Beta Thalassemia and Its Treatment Strategies

2019 ◽  
Author(s):  
Shaukat Ali ◽  
Shumaila Mumtaz ◽  
Hafiz Abdullah Shakir ◽  
Hafiz Muhammad Tahir ◽  
Tafail Akbar Mughal
Keyword(s):  
Genetic Testing ◽  
Blood Transfusion ◽  
Dna Analysis ◽  
Complete Blood Count ◽  
Globin Gene ◽  
Thalassemia Major ◽  
Beta Thalassemia ◽  
Beta Globin ◽  
Hematopoietic Stem ◽  
Thalassemia Minor

Thalassemia is genetic blood disease cause by absence or decrease of one or more of the globin chain synthesis. Beta thalassemia is characterized by one or more mutations in beta globin gene. Absence or reduced amount the of beta globin chains cause ineffective erythropoiesis which leads to anemia. Beta thalassemia has been further divided into three main forms: Thalassemia minor/silent carrier, major and intermedia. More severe form is thalassemia major in which patients depend upon blood transfusion for survival and high level of iron occur as a consequence of consistent blood transfusion. Over loaded iron invokes the synthesis of reactive oxygen species that are toxic in redundancy and triggering the impairment to vascular, endocrine and hepatic system. Thalassemia can be diagnosed and detected through various laboratory tests such as blood smear, prenatal testing (genetic testing of amniotic fluid), DNA analysis (genetic testing) and complete blood count. Treatment of thalassemia intermedia is symptomatic but it can also be managed by splenectomy and folic supplementation. While thalassemia major can be treated by transplantation of bone marrow, regular transfusion of blood and iron chelation treatment, stimulation of fetal hemoglobin production, hematopoietic stem cell transplantation and gene therapy.

scholarly journals A first case of hemoglobin Castilla [Beta 32(B14) Leu>Arg; HBB: c.98T>G] associated with [IVS-I-1 (G>A); HBB:c.92+1G>A] mutation found in a Syrian betathalassemia patient

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ahmad Shoujaa ◽  
Yasser Mukhalalaty ◽  
Hossam Murad ◽  
Faizeh Al-Quobaili
Keyword(s):  
Molecular Analysis ◽  
Clinical Case ◽  
Globin Gene ◽  
Thalassemia Major ◽  
Beta Thalassemia ◽  
Blood Transfusions ◽  
Beta Globin ◽  
First Report ◽  
Beta Thalassemia Major ◽  
First Case

Beta thalassemia (β-thal) is one of the most common worldwide inherited hemoglobinopathies. Proper identification and diagnosis of hemoglobin (Hb) variants provide a major challenge. In this report, we describe a 1-year-old boy, presented with the diagnosis of β-TM (beta thalassemia major), has received regular blood transfusions. The molecular analysis revealed the presence of rare Hb Castilla [Beta 32(B14) Leu>Arg; HBB: c.98T>G] variant associated with β0 [IVS-I-1 (G>A); AG^GTTGGT- >AGATTGGT beta0] (HBB:c.92+1G>A) Mutation in beta-globin (β-globin) gene. To our knowledge, this is the first report of Hb Castilla [Beta 32(B14) Leu>Arg] in ExonII of β-globin gene which were found in Syrian male proband. However, we should investigate abnormal hemoglobins in patients with beta thalassemia to determine whether they have involvement with β-thalassemia mutations in the clinical case of the patients or not.

scholarly journals A novel mutation in the TATA box in a Japanese patient with beta +- thalassemia

Blood ◽  
1986 ◽  
Vol 67 (2) ◽  
pp. 547-550 ◽  
Author(s):  
Y Takihara ◽  
T Nakamura ◽  
H Yamada ◽  
Y Takagi ◽  
Y Fukumaki
Keyword(s):  
Novel Mutation ◽  
Globin Gene ◽  
Japanese Woman ◽  
Tata Box ◽  
Proximal Promoter ◽  
Base Substitution ◽  
Beta Thalassemia ◽  
Beta Globin ◽  
Beta Globin Gene

Abstract A single base substitution (A-G) at position -31 within the highly conserved proximal promoter element, the TATA box, was identified in the beta-globin gene cloned from a Japanese woman with beta +- thalassemia. It appears that she is homozygous for this specific allele, as determined by haplotype analysis using seven different polymorphic sites in the beta-globin gene cluster. Transient expression of the mutant gene in COS cells revealed a 45% reduction in beta-globin RNA production, relative to normal. These results establish the functional significance of the second base of the TATA box for in vivo transcription of the human beta-globin gene.

scholarly journals A simple approach to prenatal diagnosis of beta-thalassemia in a geographic area where multiple mutations occur

Blood ◽  
1988 ◽  
Vol 71 (5) ◽  
pp. 1357-1360 ◽  
Author(s):  
SP Cai ◽  
JZ Zhang ◽  
DH Huang ◽  
ZX Wang ◽  
YW Kan
Keyword(s):  
Southern China ◽  
Globin Gene ◽  
Blot Hybridization ◽  
Geographic Area ◽  
Simple Approach ◽  
Beta Thalassemia ◽  
Beta Globin ◽  
Dot Blot ◽  
Polymerase Chain

Abstract We describe a simple approach for detecting beta-thalassemia mutations in geographic areas such as southern China where multiple mutations are known to occur. Segments of the beta-globin gene were amplified in vitro by using the polymerase chain reaction. Dot blot hybridization of the amplified DNA with oligonucleotide probes corresponding to the six mutations found in southern China could directly identify the mutations causing beta-thalassemia in the affected families. The increased number of target sequences after amplification allows the use of 35S-labeled probes, which are reusable for up to 3 months. The mutations can be determined in two days.

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