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1.
Nat Commun ; 11(1): 3778, 2020 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-32728076

RESUMO

Targeted genome editing has a great therapeutic potential to treat disorders that require protein replacement therapy. To develop a platform independent of specific patient mutations, therapeutic transgenes can be inserted in a safe and highly transcribed locus to maximize protein expression. Here, we describe an ex vivo editing approach to achieve efficient gene targeting in human hematopoietic stem/progenitor cells (HSPCs) and robust expression of clinically relevant proteins by the erythroid lineage. Using CRISPR-Cas9, we integrate different transgenes under the transcriptional control of the endogenous α-globin promoter, recapitulating its high and erythroid-specific expression. Erythroblasts derived from targeted HSPCs secrete different therapeutic proteins, which retain enzymatic activity and cross-correct patients' cells. Moreover, modified HSPCs maintain long-term repopulation and multilineage differentiation potential in transplanted mice. Overall, we establish a safe and versatile CRISPR-Cas9-based HSPC platform for different therapeutic applications, including hemophilia and inherited metabolic disorders.


Assuntos
Engenharia Celular/métodos , Edição de Genes , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/metabolismo , Animais , Sistemas CRISPR-Cas/genética , Linhagem Celular , Feminino , Regulação da Expressão Gênica , Hemofilia A/terapia , Humanos , Doenças Metabólicas/terapia , Camundongos , Regiões Promotoras Genéticas/genética , Transplante Autólogo/métodos , Transplante Heterólogo , alfa-Globinas/genética , alfa-Globinas/metabolismo
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(4): 378-383, 2020 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-32219817

RESUMO

OBJECTIVE: To determine the composition and distribution of beta-thalassemia-associated genotypes in Liuzhou area of Guangxi, China. METHODS: From January to December 2017, 13 847 individuals who came for premarital examination, maternity examination or health check were recruited with informed consent. The subjects were analyzed by reverse dot blotting (RDB) for 17 common beta-thalassemia-associated variants among the Chinese population. Individuals with inconsistent results by blood test, electrophoresis, and RDB were subjected to Sanger sequencing to detect rare variants of the beta globin gene. RESULTS: In total 2098 individuals were found to harbor beta-thalassemia-associated variants, which included 2075 heterozygotes (98.90%), 12 compound heterozygotes (0.57%) and 11 homozygotes (0.52%). CD41-42 (48.43%) and CD17 (31.45%) were the most common variants. Three hundred and thirty eight-individuals were found to also carry heterozygous variants of the alpha globin gene, with the most common types being --SEA/aa, -a3.7/aa, aCSa/aa, -a4.2/aa. Through Sanger sequencing, rare genotypes such as beta-32/betaN, betaCD41-42/betaIVS-II-5 and betaCD30/betaN were detected. CONCLUSION: Liuzhou area has a high incidence of beta-thalassemia, but with a complex variant spectrum and clinical phenotypes different from other regions. Genetic counseling and prenatal diagnosis for the carrier population is crucial for the reduction of the related birth defects. Our result may provide valuable information for the prevention and control of beta-thalassemia in this area.


Assuntos
Genótipo , Globinas beta/genética , Talassemia beta/genética , China , Feminino , Aconselhamento Genético , Variação Genética , Humanos , Mutação , Gravidez , Diagnóstico Pré-Natal , alfa-Globinas/genética , Talassemia beta/diagnóstico
3.
J Clin Pathol ; 73(8): 488-492, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31980563

RESUMO

AIMS: Thalassaemia is one of the most common genetics disorders in the world, especially in southern China. The aim of the present study was to investigate the feasibility of combining the gap-PCR and next-generation sequencing (NGS) for thalassaemia carrier screening in the Chinese population. METHODS: Blood samples were obtained from 944 prepregnancy couples; thalassaemia carrier screening was performed by using a routine haematological method and a combination of gap-PCR and NGS method. RESULTS: We found that the α thalassaemia carrier rate was 11% (207/1888); the ß thalassaemia carrier rate was 3.7% (70/1888); the composite α thalassaemia and ß thalassaemia carrier rate was 0.4% (8/1888). We also identified seven novel mutations, including HBA1: c.412A>G, -50 (G>A), HBB: c.*+129T>A, HBB: c.-64G>C, HBB: c.-180G>C, HBB: c.*+5G>A and HBB: c.-113A>G. By comparing the combined gap-PCR and NGS method, the MCV+MCH and HbA2 detection strategy showed a lower sensitivity of 61.05% (105/172) and a higher missed diagnosis ratio of 38.95% (67/172) for α thalassaemia mutations. The sensitivity was improved with the MCV+MCH and HbA2 detection screen when compared with MCV+MCH detection for ß thalassaemia (98.51% vs 85.90%). CONCLUSIONS: Our study suggests the combined gap-PCR and NGS method is a cost-effective method for the thalassaemia carrier screening, particularly for the α thalassaemia mutation carriers.


Assuntos
Talassemia alfa/genética , Talassemia beta/genética , Adulto , China , Feminino , Triagem de Portadores Genéticos/métodos , Triagem de Portadores Genéticos/normas , Genótipo , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Mutação/genética , Reação em Cadeia da Polimerase/métodos , Cuidado Pré-Concepcional , Sensibilidade e Especificidade , Adulto Jovem , alfa-Globinas/genética , Globinas beta/genética
4.
Mol Genet Genomics ; 295(2): 505-514, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31897801

RESUMO

α-thalassemia is an inherited blood disorder commonly caused by deletions or point mutations involving one or both α-globin genes. Recent studies shed new light on the critical role of upstream enhancers multi-species conserved sequences (MCSs) in the ordered regulation of α-globin gene expression. Herein, we reported two unrelated probands with deletions in α-globin genes and MCSs, respectively. The proband from Family A is a compound heterozygote carrying a known α+ mutation (-α3.7) and a novel 60.2 kb deletion causing the absence of both α-globin genes. The proband from Family B, on the other hand, is a compound heterozygote with a known α0 mutation (--SEA) and a novel deletion involving only upstream regulatory elements MCS-R1, R2 and R3, while the α-globin genes remain intact. Notably, both these two patients suffered varied extent of anemia, indicating that the loss of enhancer elements could equally lead to reduced synthesis of α-globin. Upon these observations, we then confirmed the exact breakpoints of these two novel deletions using a targeted next-generation sequencing (NGS) previously established by our group, which may enable further elucidation of the rearrangement mechanisms on these deletions and functional dissection of MCSs. Taken together, our study reports a reliable NGS-based molecular screening approach for accurate identification of copy number variations (CNVs) in the α-globin cluster and the genetic diagnosis of these two probands may help to extend the spectrum of α-thalassemia mutations in Chinese population.


Assuntos
Elementos Alu/genética , Anemia/genética , alfa-Globinas/genética , Talassemia alfa/genética , Adulto , Anemia/sangue , Anemia/patologia , Variações do Número de Cópias de DNA/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Família Multigênica/genética , Linhagem , Mutação Puntual/genética , Deleção de Sequência/genética , Talassemia alfa/sangue , Talassemia alfa/patologia
5.
J Clin Pathol ; 73(1): 14-16, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31434698

RESUMO

AIMS: Untranslated regions (UTRs) play an important role in post-transcriptional regulation of gene expression, including by modulating messenger RNA (mRNA) transport out of the nucleus, translation efficiency, subcellular localisation and stability. Any mutation in this region could alter the stability of mRNA and thereby affect protein synthesis. We analysed if a mutation located in the α complex protected region of the α1 globin gene could cause non-deletional α-thalassaemia by affecting post-transcriptional stability (mRNA stability). METHODS: A total of 14 patients without anaemia, normal or slight microcytosis and hypochromia (medium concentration haemoglobin [MCH] <27 pg) were studied. Haemoglobin subtypes were screened using capillary zone electrophoresis and ion-exchange high-performance liquid chromatography (VARIANT II ß-Thalassaemia Short Program). The most common α-globin mutations were identified by multiplex PCR (Alpha-Globin StripAssay kit) and the molecular characterisation by automatic sequencing of alpha globin genes. RESULTS: All of them shown a novel transversion mutation in nt 778 (C>A), which is located in the 3' UTR in the α complex protected region [HBA1: c.*+46C>A]. CONCLUSIONS: This mutation is in the αRNAmin binding site, so a single nucleotide substitution in this region can decrease mRNA stability by potentially compromising the binding of α-complex protein to αRNAmin, favouring the decay of α-globin mRNA via erythroid cell-enriched endoribonuclease cleavage. In this case, it is a non-deletional α-thalassaemia. However, in silico and empirical studies predicted that it could be a silent polymorphism. Functional studies should be carried out to confirm whether it is a pathological mutation or a silent polymorphism.


Assuntos
Regiões 3' não Traduzidas , Mutação , Polimorfismo Genético , Estabilidade de RNA , RNA Mensageiro/genética , alfa-Globinas/genética , Talassemia alfa/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Análise Mutacional de DNA/métodos , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex , Fenótipo , RNA Mensageiro/metabolismo , Fatores de Risco , alfa-Globinas/metabolismo , Talassemia alfa/sangue , Talassemia alfa/diagnóstico
6.
Nat Commun ; 10(1): 5412, 2019 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-31776347

RESUMO

Specific communication between gene promoters and enhancers is critical for accurate regulation of gene expression. However, it remains unclear how specific interactions between multiple regulatory elements contained within a single chromatin domain are coordinated. Recent technological advances which can detect multi-way chromatin interactions at single alleles can provide insights into how multiple regulatory elements cooperate or compete for transcriptional activation. Here, we use such an approach to investigate how interactions of the α-globin enhancers are distributed between multiple promoters in a mouse model in which the α-globin domain is extended to include several additional genes. Our data show that gene promoters do not form mutually exclusive interactions with enhancers, but all interact simultaneously in a single complex. These findings suggest that promoters do not structurally compete for interactions with enhancers, but form a regulatory hub structure, which is consistent with recent models of transcriptional activation occurring in non-membrane bound nuclear compartments.


Assuntos
Cromatina/genética , Regiões Promotoras Genéticas , alfa-Globinas/genética , Animais , Sítios de Ligação , Cromatina/metabolismo , Elementos Facilitadores Genéticos , Feminino , Loci Gênicos , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Modelos Genéticos
7.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(11): 1130-1132, 2019 Nov 10.
Artigo em Chinês | MEDLINE | ID: mdl-31703143

RESUMO

OBJECTIVE: To analyze the hematological characteristics of a patient with Hb Ottawa in conjunction with ß -thalassemia. METHODS: Peripheral blood samples from the proband and her parents were collected and subjected to red blood cell analysis and hemoglobin electrophoresis. Genotypes of α - and ß -globin genes were also analyzed. RESULTS: The proband and her mother were both heterozygotes for Hb Ottawa and ß -thalassemia variant IVS II-654, and presented with typical ß -thalassemia trait featuring hypochromic microcytic anemia. An abnormal hemoglobin band was detected upon electrophoresis. CONCLUSION: Co-existence of Hb Ottawa and ß -thalassemia may not aggravate the phenotype.


Assuntos
Hemoglobinas Anormais/genética , Talassemia beta/genética , Feminino , Testes Genéticos , Heterozigoto , Humanos , alfa-Globinas/genética , Globinas beta/genética
8.
Hemoglobin ; 43(4-5): 241-244, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31690131

RESUMO

Although mutations causing α-thalassemia (α-thal) are mainly larger deletions involving one or both of the duplicated α-globin genes, point mutations are not rare. We have identified a novel mutation of the translation initiation codon of the α2-globin gene with DNA sequencing and allele-specific multiplex ligation-dependent probe amplification (MLPA) in a Chinese family. RNA analysis was performed with reverse transcription-MLPA (RT-MLPA). A novel mutation at the translation initiation codon of the α2-globin gene (HBA2: c.3G>C) was identified. The proband and his father, who were both carriers of this mutation, had a hematological phenotype of mild α+-thalassemia (α+-thal) trait with low-normal limit of mean corpuscular volume (MCV) and normal Hb A2. RNA analysis showed markedly decreased levels of α-globin mRNA and the presence of a small amount of mutant mRNA. The HBA2: c.3G>C mutation most likely caused α-thal by lowering levels of wild α-globin chain. Our study increases the mutation spectrum of α-thal.


Assuntos
Códon de Iniciação/genética , Mutação Puntual , alfa-Globinas/genética , Talassemia alfa/genética , Grupo com Ancestrais do Continente Asiático , Sequência de Bases , Índices de Eritrócitos , Família , Feminino , Hemoglobina A2/genética , Hemoglobinas Anormais/genética , Humanos , Masculino , Fenótipo
9.
Hemoglobin ; 43(4-5): 286-288, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31650882

RESUMO

Here we report a 67-year-old Chinese male carrying an unstable novel hemoglobin (Hb) variant in compound heterozygosity with the - -SEA (Southeast Asian) α-thalassemia (α-thal) deletion. Hemoglobin analysis by capillary electrophoresis (CE) revealed a rapid degradation feature of the variant. Sanger sequencing of the Hb gene revealed a novel homozygous mutation in exon 2 of the α1-globin gene [α52(E1)Ser→Cys (TCT>TGT); HBA1: c.158C>G]. We named this novel variant Hb Dongguan for the place of origin of the proband. Additionally, gap-polymerase chain reaction (gap-PCR) indicated the presence of the heterozygous - -SEA α-thal deletion.


Assuntos
Hemoglobinas Anormais/genética , Heterozigoto , alfa-Globinas/genética , Talassemia alfa/genética , Idoso , Grupo com Ancestrais do Continente Asiático , Eletroforese Capilar , Homozigoto , Humanos , Masculino , Mutação , Estabilidade Proteica , Deleção de Sequência
10.
Mol Cell Neurosci ; 100: 103398, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31472221

RESUMO

Neurogenesis is driven by spatially and temporally regulated proliferation of neuronal progenitor cells that generates enormous number of assorted neurons to drive the complex behavior of an organism. Drosophila nervous system provides an advantageous model for identification and elucidation of the functional significance of the novel gene(s) involved in neurogenesis. The present study attempts to investigate the role(s) of globin1 (glob1) in the development and maintenance of the nervous system in Drosophila. It is increasingly clear now that globin genes play important role(s) in the various biological phenomena. The vertebrate neuroglobin has been reported to profoundly express in neuronal tissues and provides neuroprotection. We noted ubiquitous presence of Glob1 in the developing neuronal tissues with enhanced concentration throughout the VNC which comprises of midline cell clusters, which subsequently forms numerous types of progenitor cells and finally differentiate into specific neurons of the nervous system. Ubiquitous or pan-neuronal downregulation of glob1 causes partial lethality and mis-positioning of various neural-progenitor cells present in the embryonic midline cell clusters. Subsequently, profound expression of Glob1 was noted in the outer proliferation center of larval brain and photoreceptor axons of optic stalk. The overall arrangement of photoreceptor axons and stereotype positioning of neuroblast cells present in the central region of the brain were severally affected due to reduced expression of glob1. In addition, such larvae and surviving adults develop significant neuro-muscular disabilities. For the first time, our study suggests a novel role of glob1 in development and maintenance of the nervous system adding a new dimension to the functional significance of the multi-tasking glob1 gene in Drosophila.


Assuntos
Proteínas de Drosophila/genética , Gânglios dos Invertebrados/metabolismo , Neurogênese , alfa-Globinas/genética , Animais , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Gânglios dos Invertebrados/citologia , Gânglios dos Invertebrados/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , alfa-Globinas/metabolismo
11.
Clin Biochem ; 74: 80-85, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31493379

RESUMO

Hb variants are structurally abnormal haemoglobins which can originate a wide range of phenotypes from clinically silent conditions to very severe disorders. In many cases, diagnosis is very difficult due to the instability of Hb mutants or the occurrence of misleading symptoms, such as cyanosis or hypoxia. Here we report the case of a young female with undiagnosed chronic haemolytic anaemia and low oxygen saturation in the absence of respiratory distress. High performance liquid chromatography showed the occurrence of an abnormal peak in the HbA2 region, which disappeared few days after blood sampling. Genetic analysis of both α genes revealed the -α3.7 deletion in heterozygous state and a novel mutation c.130 T > C leading to the substitution of Phenylalanine at codon 43 with Leucine in the α1 gene. This substitution originated a new Hb variant, named Hb Vanvitelli, with a molecular mass of 15,092.2 ±â€¯0.4 Da. Biochemical and laboratory tests described a hyper unstable Hb variant with altered oxygen affinity that was clinically significant only when co-inherited with genetic defects affecting the α2 locus. This case highlights the genetic complexity and diagnostic pitfalls of Hb variants, defined "experiments of nature" which can generate severe clinical conditions.


Assuntos
Anemia Hemolítica/diagnóstico , Anemia Hemolítica/genética , Hemoglobinas Anormais/genética , Deleção de Sequência , alfa-Globinas/genética , Adolescente , Sequência de Aminoácidos/genética , Substituição de Aminoácidos/genética , Anemia Hemolítica/sangue , Cromatografia Líquida , Doença Crônica , Códon/genética , Feminino , Testes Genéticos , Heterozigoto , Humanos , Itália , Espectrometria de Massas , Oximetria , Oxigênio/sangue , Linhagem , Fenótipo
12.
Yi Chuan ; 41(8): 669-676, 2019 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-31447418

RESUMO

ß-thalassemia (ß-thal) is a fatal and disabling inherited blood disorder with diverse phenotypes. The same or similar genotype of ß-thal can manifest variable clinical severities. It is the hotspot and emphasis in the field of hematopathy and genetic diseases to explore genetic modifiers that influence the phenotype of ß-thal. This review illustrates the deteriorating and amelioratig modifiers from two aspects: genotypes of α-globin and quantitative trait locus of fetal hemoglobin (Hb F). Variations of transcription factors which reactive the γ-globin gene expression and ß-globin cluster cis-acting elements were introduced emphatically. Finally, clinical applications and future development prospects of ß-thal genetic modifiers are introduced by examples.


Assuntos
Talassemia beta/genética , Hemoglobina Fetal/genética , Genótipo , Humanos , Fenótipo , Fatores de Transcrição/genética , alfa-Globinas/genética , Globinas beta/genética , gama-Globinas/genética
13.
Acta Haematol ; 142(3): 132-141, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31352439

RESUMO

Thalassaemias are the most common inherited autosomal recessive single gene disorders characterised by chronic hereditary haemolytic anaemia due to absence or reduced synthesis of one or more of the globin chains. Haemoglobin E (HbE)-ß-thalassaemia is the genotype responsible for approximately one-half of all cases of severe ß-thalassaemia worldwide. This study proposes to evaluate response of hydroxyurea in reducing transfusion requirements of severe HbE-ß-thalassaemia patients, and its correlation with foetal haemoglobin (HbF) level and α-mutation. Hydroxyurea was started at a baseline dose in 82 transfusion-dependent HbE-ß-thalassaemia patients. HbF levels and %F-cells were measured. ß-Thalassaemia mutations and α-globin gene deletions and triplications were detected by amplification refractory mutation system (ARMS)-polymerase chain reaction (PCR) and Gap-PCR, respectively. Patients were categorised as good (41.5%), moderate (31.7%), and poor responders (26.8%) based on their decrease in transfusion requirements. Nine patients were excellent responders who became transfusion independent. The mean increase in HbF levels and %F-cells after therapy was correlated with decrease in transfusion requirements. Patients having a deletion of the α-globin gene were better responders. The response was proportional to the number of α-globin gene deletions. We conclude that hydroxyurea treatment decreases transfusion requirements, and the response correlates with α-globin gene deletions.


Assuntos
Transfusão de Sangue , Deleção de Genes , Hemoglobina E/metabolismo , Hidroxiureia/administração & dosagem , alfa-Globinas/genética , Talassemia beta , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Talassemia beta/sangue , Talassemia beta/genética , Talassemia beta/terapia
14.
Hemoglobin ; 43(2): 107-111, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31304855

RESUMO

α-Thalassemia (α-thal) is one of the most common genetic disorders worldwide. The aim of this study was to investigate for the first time the α-thal mutation spectrum in the Lak population living in Lorestan Province, Iran. One hundred and seventy-six α-thal carriers participated in the study. Multiplex gap-polymerase chain reaction (gap-PCR), amplification refractory mutation system (ARMS)-PCR and direct sequencing were used for the detection of different mutations on the α-globin (HBA1 and HBA2) genes. A total of 11 different mutations was identified. The -α3.7 (rightward; NG_000006.1: g.34164_37967del3804) deletion was observed most frequently (56.35%), followed by α-5 ntα (HBA2: c.95+2_95+6delTGAGG), αpolyA2α (HBA2: c.*92A>G) and - -MED I (NG_000006.1: g.24664_41064del16401), with frequencies of 15.47, 9.39, and 6.08%, respectively. These four mutations accounted for more than 87.0% of the total mutated alleles. Moreover, 19 different genotypes were identified. The types and distribution pattern of the mutations identified in this study, in comparison with other studies conducted in Iran, was most similar to the Kurdish population of Kermanshah Province, Iran. Due to the lack of information on α-thal in Lorestan Province, it was not possible to compare the mutation spectrum in the Lur and Lak populations. In conclusion, our results may help in setting up a strategy for an α-thal screening program and genetic counseling in the Lak people.


Assuntos
Mutação , alfa-Globinas/genética , Talassemia alfa/genética , Genótipo , Heterozigoto , Humanos , Irã (Geográfico)/epidemiologia , Irã (Geográfico)/etnologia , Análise de Sequência de DNA/métodos , Talassemia alfa/etnologia
15.
Int J Lab Hematol ; 41(5): 650-656, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31271507

RESUMO

INTRODUCTION: Thalassemias and hemoglobinopathies are the most prevalent inherited anemias detected in South East Asians. These disorders represent not only a clinical health problem but also a socioeconomic problem for this region. Regarding the prevention and control of thalassemias and hemoglobinopathies in the Lao PDR, screening and diagnostic strategies should be strongly considered. The knowledge about the prevalence and molecular genotyping of thalassemias and hemoglobinopathies among the Lao Loum group, which includes the majority of Lao people, is now limited, making the prevention and control of thalassemias difficult. METHODS: This study aimed to determine the prevalence of thalassemia among Lao Loum subjects of reproductive age. Multiplex gap PCR and direct sequencing were used to investigate the mutations of α-globin and ß-globin genes. RESULTS: Thalassemias and hemoglobinopathies were detected in 154 of 354 (43.50%) patients, and 22 different genotypes were identified in this cohort. Remarkably, high frequencies of hemoglobin E, α0 -thalassemia (--SEA ), and α+ -thalassemia (-α3.7 ) were noted. A variety of hematologic features was observed, including co-inheritance of heterozygous HbE and heterozygous α-thalassemia, which was associated with significantly lower levels of MCV and MCH values than those observed in typical HbE heterozygotes. Female participants who were heterozygous for ß0 or co-inheritance of heterozygous ßE with heterozygous α-thalassemia exhibited mild anemia. CONCLUSION: Our data show that thalassemias and hemoglobinopathies have become health problems imposing a serious burden in the Lao PDR. Prevention programs aimed at decreasing the incidence of severe thalassemia diseases should be designed and initiated.


Assuntos
Hemoglobina E/genética , Hemoglobinopatias/genética , Mutação , alfa-Globinas/genética , Talassemia alfa/genética , Talassemia beta/genética , Adolescente , Feminino , Frequência do Gene , Testes Genéticos/métodos , Genótipo , Hemoglobinopatias/diagnóstico , Hemoglobinopatias/epidemiologia , Humanos , Laos/epidemiologia , Masculino , Prevalência , Adulto Jovem , Talassemia alfa/diagnóstico , Talassemia alfa/epidemiologia , Talassemia beta/diagnóstico , Talassemia beta/epidemiologia
16.
Mol Biol Rep ; 46(5): 5041-5048, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31273613

RESUMO

Thalassemia is one of the most common monogenic hereditary disorders. Despite noticeable advances made in prevention strategies, it is still highly prevalent in the Iranian population. A key approach to management and early diagnosis of the disease is through revealing the regions with high prevalence and determining common genetic and phenotypic diversity. In the current study Hemoglobin H (HbH) disease patients were analyzed as the most common form of thalassemia intermedia in Iran. A total of 80 patients suspected of being thalassemic according to their mild to moderate anemia, microcytosis and normal iron levels were included in this study at the hemoglobinopathy and thalassemia center of Ahvaz University of Medical Science. Patients were analyzed for hematological parameters and HbH mutations using Multiplex Gap Polymerase Chain Reaction and Multiplex Amplification Refractory Mutation System. Twelve mutations were detected in the studied population. The most common genotype was -α3.7/--MED (45%) followed by Homozygote αPoly A2 (17.5%). A total of ten different alpha-globin (α-globin) mutations were observed in patients which --MED, being the most common mutation (26.27%), followed by -α3.7 (24.37%) and αpolyA2(A>G) (18.12%). Hematological parameters such as Hb, MCV, MCH and HbH were assessed and results showed that they varied significantly among genotypes, adjusted to age and gender. This study reveals a highly diverse range of HbH patients different from what was thought in terms of both genotype and phenotype in the Khuzestan region of Iran. These findings could contribute to improve the thalassemia managing policies in this province.


Assuntos
Talassemia/genética , Talassemia alfa/genética , Adolescente , Adulto , Feminino , Estudos de Associação Genética/métodos , Genótipo , Humanos , Irã (Geográfico)/epidemiologia , Masculino , Mutação , Fenótipo , Talassemia/metabolismo , Adulto Jovem , alfa-Globinas/genética , alfa-Globinas/metabolismo , Talassemia alfa/metabolismo , Talassemia beta/genética
17.
J Pak Med Assoc ; 69(7): 959-963, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31308562

RESUMO

OBJECTIVE: To find frequency ofalpha Thalsaemia nhomozygous beta Thalsaemia patients, and to se any difernce infrequency and age ofirst ransfusion and mean haemoglobin concentration. METHODS: The single-centred, escriptive cros-sectional study was conducted athe National Instiute of Blod Disease and Bone Marow Transplantaion, Karchi, from June 1,2012, to May 31, 2013. Patients of homozygous beta halsaemia, diagnosed by polymerase chain reaction, wer tested for coinheritance of alpha Thalsaemia nd foetal haemoglobin XMN1 polymorphism using polymerase chain reaction. SPS 17 was used for dat anlysi. RESULTS: Of the 286 patients, 19(41.6%) wer males, and 9(34.6%) showed coinheritance ofalpha thalsaemia. In the coinheritance group, 50(50%) and 1(1%) patients recived 1-20 and 21-40 times transfusions per year espectively, while inthe non-coinheritance group, the coresponding numbers wer 125(67%) and 27(14.%). Overal, 73(25.%) patients had nevr ben transfused, including 38(13.%) patients inthe alpha Thalsaemia group. XMN1 polymorphism was found in 86(41%) ofthe 208 patients who wer tested and anlysed on this count. CONCLUSIONS: Alpha thalsemia was presnt inmore than one-third homozygous beta halsemia patients.


Assuntos
Talassemia alfa/epidemiologia , Talassemia beta/epidemiologia , Adolescente , Transfusão de Sangue , Criança , Pré-Escolar , Comorbidade , Feminino , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Paquistão/epidemiologia , alfa-Globinas/genética , Talassemia alfa/sangue , Talassemia alfa/genética , Talassemia alfa/terapia , Globinas beta/genética , Talassemia beta/sangue , Talassemia beta/genética , Talassemia beta/terapia
18.
Hemoglobin ; 43(2): 112-115, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31223040

RESUMO

α-Thalassemia (α-thal) is a common hemoglobinopathy mainly caused by deletion of one or both α-globin genes. We describe an autochthonous Belgian family diagnosed with α-thal trait. Molecular analysis revealed a novel large deletion of at least 170 kb between 226.68 kb (0.2 Mb) and 402.68 kb (0.4 Mb) from the telomere of 16p, leaving the subtelomeric region intact. The deletion includes both α-globin genes (HBA1 and HBA2) but also flanking genes possibly related to non hematological effects: HBQ1, LUC7L, ITFG3, RGS11, ARHGDIG, PDIA2 and AXIN1. These genes are not contained in the region (0.9 and 1.7 Mb from the telomere of 16p) associated with α-thal intellectual disability (ATR-16) syndrome. However, further research is necessary to exclude other potential effects than α-thal in patients with a large deletion at 0.2-0.4 Mb from the telomere of 16p. Genetic counseling is important for carriers of this deletion as homozygosity for the α-globin (- -/) haplotype may lead to Hb Bart's (γ4) hydrops fetalis syndrome.


Assuntos
Deleção de Sequência/genética , Talassemia alfa/genética , Bélgica , Família , Hemoglobinas Anormais , Heterozigoto , Humanos , Hidropisia Fetal , Telômero/genética , alfa-Globinas/genética
19.
Hemoglobin ; 43(2): 122-125, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31145010

RESUMO

A new unstable hemoglobin (Hb) variant, named Hb Aalesund, was detected during Hb A1c measurement in a patient with a nearly compensated hemolytic anemia. Sequencing of the α-globin genes revealed a 7 bp deletion in exon 3 of the HBA2 gene (HBA2: c.400_406delAGCACCG) (NM_000517.4) causing a frameshift and a premature termination codon (PTC) two positions downstream. Apparently, the transcript bypassed nonsense-mediated decay (NMD), and a truncated protein was translated. The unstable Hb variant presumably underwent rapid denaturation, as heterozygosity of Hb Aalesund was associated with mild hemolytic anemia. In addition, the Hb variant interfered with Hb A1c measurement by cation exchange high performance liquid chromatography (HPLC), causing a falsely high Hb A1c result when using the Bio-Rad D10™ Hemoglobin Analyzer fast Hb A1c Program.


Assuntos
Anemia Hemolítica/genética , Variação Genética , Hemoglobina A Glicada/análise , Hemoglobinas Anormais/genética , alfa-Globinas/genética , Cromatografia Líquida de Alta Pressão/métodos , Códon sem Sentido/genética , Heterozigoto , Humanos , Noruega , Estabilidade Proteica , Análise de Sequência de DNA , Deleção de Sequência/genética
20.
BMC Med Genet ; 20(1): 74, 2019 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-31060505

RESUMO

BACKGROUND: α-thalassaemia is an inherited blood disorder caused by mutations in the α-globin gene cluster. Recognizing the pathogenic α-globin gene mutations associated with α-Thalassemia is of significant importance to thalassaemia's diagnosis and management. METHODS: A family with α-thalassaemia from Fujian, China was recruited for this study. The phenotype was confirmed through haematological analysis. Commercially available Gap-PCR genotypic methods were employed to identify the known deletions causing α-thalassemia. MLPA analysis was used to study the novel mutations; this was then confirmed through DNA sequencing and bioinformatics analysis. RESULTS: The proband of the family belonged to Southeast Asian type (--SEA) thalassaemia. None of the known mutations associated with α-thalassaemia were detected in this family's genetics, whereas a novel 6.9 kb deletion (16p13.3 g.29,785-36,746) covering the α2 gene on the globin gene cluster was identified with MLPA and confirmed through Sanger Sequencing. This data led us to propose a novel pathogenic deletion associated with α-thalassemia: -α6.9 /--SEA. CONCLUSIONS: A novel α-thalassaemia deletion was identified in members of a Chinese family and subsequently analyzed. This finding has helped broaden the spectrum of pathogenic mutations leading to the development of α-thalassaemia, paving the way for improved disease diagnosis and management.


Assuntos
Deleção de Genes , alfa-Globinas/genética , Talassemia alfa/genética , Adulto , China , Grupos Étnicos , Feminino , Humanos , Masculino , Mutação
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