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Introduction: Growth Hormone Deficiency (GHD) is a rare disease marked by a complete or partial reduction in the production of growth hormone. Vitamin D deficiency is frequent and may be associated with several pathologies. However, the association between GHD and vitamin D deficiency has not been extensively studied. This study aimed to analyse VDR gene polymorphisms related to vitamin D status to ensure better care for patients with GHD. Material and methods: A case-control study was conducted at the Children's Hospital of Tunis in collaboration with the Farhat Hached's Hospital of Sousse, including patients with GHD and healthy subjects. Genetic analysis of the VDR gene polymorphisms was performed using PCR-RFLP technique. Haplotypes were examined with Haploview software, while statistical analyses were carried out using SPSS and R programming language. Results: Our study revealed significant differences in vitamin D (p = 0, 049) and calcium concentrations between patients and healthy subjects, which were lower in the GHD group (p = 0,018). A comparison of allelic and genotypic frequencies of the five polymorphisms indicated an association between the FokI polymorphism and GHD. Furthermore, significant difference was observed between the ApaI genotypes and PTH (p = 0,019) and ALP (p = 0,035). FokI genotypes were associated with phosphorus (p = 0,021). Additionally, One haplotype, CTAGT, exhibited a significant difference between the patients and healthy subjects (p = 0,002). Conclusion: Our study findings indicate that hypovitaminosis D is common among patients with GHD, even when undergoing treatment with rhGH. This underscores the critical importance of vitamin D supplementation during treatment.
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Familial Hypophosphatasia presents a complex diagnostic challenge due to its wide-ranging clinical manifestations and genetic heterogeneity. This study aims to elucidate the molecular underpinnings of familial Hypophosphatasia within a Tunisian family harboring a rare c.896 T > C mutation in the ALPL gene, offering insights into genotype-phenotype correlations and potential therapeutic avenues. The study employs a comprehensive approach, integrating biochemical examination, genetic analysis, structural modeling, and functional insights to unravel the impact of this rare mutation. Genetic investigation revealed the presence of the p.Leu299Pro mutation within the ALPL gene in affected family members. This mutation is strategically positioned in proximity to both the catalytic site and the metal-binding domain, suggesting potential functional consequences. Homology modeling techniques were employed to predict the 3D structure of TNSALP, providing insights into the structural context of the mutation. Our findings suggest that the mutation may induce conformational changes in the vicinity of the catalytic site and metal-binding domain, potentially affecting substrate recognition and catalytic efficiency. Molecular dynamics simulations were instrumental in elucidating the dynamic behavior of the tissue-nonspecific alkaline phosphatase isozyme (TNSALP) in the presence of the p.Leu299Pro mutation. The simulations indicated alterations in structural flexibility near the mutation site, with potential ramifications for the enzyme's overall stability and function. These dynamic changes may influence the catalytic efficiency of TNSALP, shedding light on the molecular underpinnings of the observed clinical manifestations within the Tunisian family. The clinical presentation of affected individuals highlighted significant phenotypic heterogeneity, underscoring the complex genotype-phenotype correlations in familial Hypophosphatasia. Variability in age of onset, severity of symptoms, and radiographic features was observed, emphasizing the need for a nuanced understanding of the clinical spectrum associated with the p.Leu299Pro mutation. This study advances our understanding of familial Hypophosphatasia by delineating the molecular consequences of the p.Leu299Pro mutation in the ALPL gene. By integrating genetic, structural, and clinical analyses, we provide insights into disease pathogenesis and lay the groundwork for personalized therapeutic strategies tailored to specific genetic profiles. Our findings underscore the importance of comprehensive genetic and clinical evaluation in guiding precision medicine approaches for familial Hypophosphatasia.
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Fosfatase Alcalina , Hipofosfatasia , Linhagem , Humanos , Hipofosfatasia/genética , Hipofosfatasia/diagnóstico , Masculino , Feminino , Fosfatase Alcalina/genética , Fosfatase Alcalina/química , Tunísia , Adulto , Simulação de Dinâmica Molecular , Domínio Catalítico/genética , Mutação , Estudos de Associação Genética/métodos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Hemoglobinopathies, inherited disorders of hemoglobin (Hb), are the most common hereditary monogenic diseases of the red cell in the world. Few studies have been conducted on hemoglobinopathies in Mauritania. Therefore, the aim of this work is to establish the molecular and epidemiological basis of hemoglobinopathies in a cohort of Mauritanian patients and to determine the haplotype of the ß-globin gene cluster in sickle cell subjects. METHODS: The molecular screening of Hb disorders in 40 Mauritanian patients was done by a polymerase-restriction fragment length polymorphism (RFLP) for the sickle cell disease (SCD) mutation, a PCR/sequencing method for ß-thalassemia mutations, and by the multiplex polymerase chain reaction method for the α-thalassemia. The exploration of eight polymorphic sites (SNPs) within the ß-globin gene cluster was conducted by PCR/RFLP method, to identify the HbS haplotypes from the sickle cell subjects. RESULTS: The epidemiological study of our patients showed a high incidence in the Senegal River area (52.5%) and a high ethnic prevalence for the Heratin (47.5%) and the Pular (35%). Molecular study allowed us to identify eight different mutations in our sample analyzed. They are respectively: HbS (HBB:c.20A>T) (68.75%), Cd44 -C (HBB:c.135delC) (8.75%), -29A>G (HBB:c.-79A>G) (4.8%), -α-3.7 (g.34164_37967del3804) (3.75%), IVS-II-849A>G (HBB:c.316-2A>G) (2.25%) and Cd24T>A (HBB:c.75T>A), Hb Siirt (HBB:c.83C>G) and HbC (HBB:c.19G>A) each with (1.25%). Six different haplotypes are being explored among the SCD subjects with the Senegal haplotype as the most prevalent (66.7%), followed by Benin (10%), Arab-Indians (6.7%), Bantu (3.3%), and two atypical haplotypes. CONCLUSION: Our findings enrich the epidemiological data in our population and could contribute to the establishment of a strategy of prevention and management through screening, genetic counseling, and prenatal diagnosis of Hemoglobinopathies in the Mauritanian population.
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Anemia Falciforme , Hemoglobinopatias , Talassemia alfa , Anemia Falciforme/epidemiologia , Anemia Falciforme/genética , Hemoglobinopatias/diagnóstico , Hemoglobinopatias/epidemiologia , Hemoglobinopatias/genética , Humanos , Mauritânia/epidemiologia , Talassemia alfa/genética , Globinas beta/genéticaRESUMO
OBJECTIVES: This study aims to describe the molecular variability in the SFTPC gene in a childhood chronic respiratory disease, asthma, in the Tunisian population and to identify the implications based on a case-control study of p.Thr138Asn (T138N) and p.Ser186Asn (S186N) variants. METHODS: We used direct sequencing for the genotyping of the SFTPC gene within 101 asthmatic children. The study of T138N and S186N variants in 110 controls is conducted by the PCR-RFLP technique. RESULTS: The molecular study revealed 26 variants including 24 intronic variations and 2 exonic variations (T138N and S186N) with respective frequencies of 16.8% and 18.3%. We conducted a case-control study of the two identified exonic variations. A different genotypic and allelic distribution between the two groups was noted. Only the T138N polymorphism showed a significant association with asthma disease (p < 1 0 -3). Statistical analysis elaborated four haplotypes with the following frequencies in patients vs controls: 138Thr-186Ser (79.5% vs 57.6%), 138Thr-186Asn (3.7% vs 7.8%), 138Asn-186Thr (2.2% vs 20.2%) and 138Asn-186Asn (14.6% vs 14.4%). A significant difference (p < 1 0 -3) was highlighted in haplotype distribution. The 138Asn-186Ser (OR [95%CI] = 0.14[0.04-0.54], p = 0.004, R2=0.93) and 138Thr-186Asn (OR [95%CI] = 0.35[0.12-0.54], p = 0.047, R2=0.88) haplotypes showed a negative association with asthma which may constitute a protective factor against the disease. CONCLUSION: In Tunisia, this work constitutes the first report interested in the SFTPC gene and highlights the genetic variability of the SFTPC gene in asthma. Therefore, the case-controls analysis may be useful in the study of surfactant proteins dysfunction in chronic respiratory disease at an early age.
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Asma , Proteína C Associada a Surfactante Pulmonar/genética , Tensoativos , Asma/genética , Estudos de Casos e Controles , Criança , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Doenças Pulmonares Intersticiais , Polimorfismo Genético , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Thalassemia is one of the most prevalent worldwide autosomal recessive disorders characterized by a great molecular and clinical expression heterogeneity. Alpha and beta-thalassemia are the main two types observed in case of mutations affecting alpha and beta-globin genes respectively. Delta-thalassemia is noted when mutations occur on the delta-globin gene. In Tunisia, ß-thalassemia prevalence is estimated at 2.21% of carriers. However, few reports investigated the delta-globin gene. OBJECTIVES: In this work, we aimed to perform a molecular study to help define the molecular spectrum of δ-thalassemia mutations in Tunisia. PATIENTS AND METHODS: The study involved 7558 patients among whom we selected 179 individuals with abnormal HbA2 values or fractions. Hemoglobin analysis was performed using Capillary electrophoresis (CE) and high-performance liquid chromatography (HPLC). DNA sequencing was performed on ABI prism 310 Genetic Analyzer Applied Biosystems. CUPSAT (Cologne University Protein Stability Analysis Tool) was used for the prediction of protein stability changes upon missense mutations and mutants were modeled via DeepView-SwissPdbViewer and POV-Ray softwares for molecular dynamics simulation studies. RESULTS: We identified four mutations: HbA2-Yialousa described for the first time in Tunisia ( in 72.72% of cases) and 3 mutations reported for the first time in the world: (i) c.442 T > C Stop147Arg ext 15aa-stop observed in 18.18% of cases, (ii) c.187 G > C (Ala62Pro) noted in 4.54% of cases and (iii) c.93-1G > C found in 4.54% of cases. CONCLUSION: Our data provide genetic basis that would be especially useful in screening for beta-thalassemia trait during delta-beta thalassemia associations.
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Globinas delta/genética , Talassemia delta/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Sequência de Bases/genética , Feminino , Frequência do Gene/genética , Hemoglobina A2/genética , Hemoglobinas/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Análise de Sequência de DNA/métodos , Tunísia/epidemiologia , Globinas beta/genética , Talassemia beta/genética , Globinas delta/metabolismo , Talassemia delta/metabolismoRESUMO
Congenital atransferrinemia is an extremely rare autosomal recessive disorder resulting in the complete absence or extremely reduced amount of transferrin. In this study, we describe the first case of congenital atransferrinemia in Tunisia and the 18th patient in the reported data. The patient was referred to our hospital to explore a severe hypochromic and microcytic anemia. The laboratory evaluation including hematological and biochemical examination was performed in the proband and her parents. All exons of the transferrin gene were PCR amplified. The products were screened for mutations by direct sequencing. Based on laboratory and clinical findings, diagnosis of congenital atransferrinemia was confirmed. DNA sequencing revealed the presence of a novel homozygous deletion (c.293-63del) in the intron 13. This mutation is predicted to generate a higher score cryptic branch point leading to the production of an altered mRNA molecule. The second previously reported missense mutation p.Arg609Trp. Crystallographic structure analyzes demonstrate that the mutation would probably lead to significant conformational change not allowing the expression of transferrin protein. Current molecular characterization of this novel transferrin abnormality puts to the proof the variability in onset, first blood transfusion, and phenotypic expression in atransferrinemic patients.
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Erros Inatos do Metabolismo dos Metais/genética , Mutação , Sítios de Splice de RNA , Transferrina/deficiência , Transferrina/genética , Feminino , Homozigoto , Humanos , Lactente , Erros Inatos do Metabolismo dos Metais/patologia , Domínios Proteicos , Transferrina/química , Transferrina/metabolismoRESUMO
Introduction and Objectives: Asthma is a complex genetic disorder. Several genes have been found associated with asthma. The cystic fibrosis transmembrane conductance regulator (CFTR) gene is one of them. The aim of this study was to perform a comparative analysis of the genotype and allele frequency distributions of the biallelic marker M470V within the CFTR gene on mutant and wide chromosomes. Patients and methods: The molecular approach consists in the genotyping of the M470V marker by the PCR-RFLP technique in 105 asthmatic patients, aged between four months and 17 years, and 105 healthy subjects. Results: We found a significant difference in the genotype frequencies between the two studied groups (chi2 = 9.855, P = 0.007). The V/V genotype was over represented in the asthmatic group as compared to the controls (32.38% vs. 16.19%). Whereas, the M/V genotype is more frequent in healthy subjects (40.95% vs. 28.71%). We also noted a significant difference in allelic distribution of M470V with associated diseases (chi2 = 9.610, P = 0.022). Conclusions: The present study is the first report on the distribution of the M470V polymorphism in asthmatic Tunisian patients. We noticed that the M470V variant could modulate the clinical phenotype of asthmatic patients. This preliminary study will establish the molecular basis of this disease in Tunisia
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Humanos , Masculino , Lactente , Pré-Escolar , Criança , Adolescente , Asma/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Genótipo , Mutação/genética , Frequência do Gene , Estudos de Associação Genética , FenótipoRESUMO
INTRODUCTION AND OBJECTIVES: Asthma is a complex genetic disorder. Several genes have been found associated with asthma. The cystic fibrosis transmembrane conductance regulator (CFTR) gene is one of them. The aim of this study was to perform a comparative analysis of the genotype and allele frequency distributions of the biallelic marker M470V within the CFTR gene on mutant and wide chromosomes. PATIENTS AND METHODS: The molecular approach consists in the genotyping of the M470V marker by the PCR-RFLP technique in 105 asthmatic patients, aged between four months and 17 years, and 105 healthy subjects. RESULTS: We found a significant difference in the genotype frequencies between the two studied groups (χ2=9.855, P=0.007). The V/V genotype was over represented in the asthmatic group as compared to the controls (32.38% vs. 16.19%). Whereas, the M/V genotype is more frequent in healthy subjects (40.95% vs. 28.71%). We also noted a significant difference in allelic distribution of M470V with associated diseases (χ2=9.610, P=0.022). CONCLUSIONS: The present study is the first report on the distribution of the M470V polymorphism in asthmatic Tunisian patients. We noticed that the M470V variant could modulate the clinical phenotype of asthmatic patients. This preliminary study will establish the molecular basis of this disease in Tunisia.
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Asma/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Genótipo , Mutação/genética , Adolescente , Criança , Pré-Escolar , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Lactente , Masculino , Fenótipo , Polimorfismo Genético , TunísiaRESUMO
PURPOSE: Clopidogrel non-responsiveness is multifactorial; several genetic and non-genetic factors may contribute to impaired platelet inhibition. The goal of this study is to determine the effect of the cytochrome P450 CYP2C19*2 polymorphism on the platelet response to clopidogrel in patients with and without diabetes mellitus (DM). METHODS: We conducted an observational study in patients with coronary artery disease and consequent exposure to clopidogrel therapy (75 mg/day for at least 7 consecutive days). We have analyzed two groups of patients: group I (DM patients) and group II (non-diabetes mellitus patients). Platelet reactivity was assessed by the VerifyNow P2Y12 assay and high on clopidogrel platelet reactivity (HPR) was defined as P2Y12 reaction units (PRU) ≥ 208. Genotyping for CYP2C19*2 polymorphism was performed by PCR-RFLP. RESULTS: We have included 150 subjects (76 DM and 74 non-diabetes mellitus patients). The carriage of CYP2C19*2 allele, in DM patients, was significantly associated to HPR (odds ratio (OR) 4.437, 95% confidence interval (CI) 1.134 to 17.359; p = 0.032). Furthermore, 8.4% of the variability in percent inhibition by clopidogrel could be attributed to CYP2C19*2 carrier status. However, in non-diabetes mellitus patients, there was no significant difference in platelet response to clopidogrel according to the presence or absence of CYP2C19*2 allele carriage (OR 1.260, 95% CI 0.288 to 5.522; p = 0.759). CONCLUSIONS: Our study suggests that the carriage of CYP2C19*2 polymorphism, in DM patients, might be a potential predictor of persisting HPR in these high-risk individuals. TRIAL REGISTRATION: Clinical Trials.gov NCT03373552 (Registered 13 December 2017).
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Clopidogrel/uso terapêutico , Doença da Artéria Coronariana/tratamento farmacológico , Citocromo P-450 CYP2C19/genética , Diabetes Mellitus/tratamento farmacológico , Angiopatias Diabéticas/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Adulto , Idoso , Plaquetas/efeitos dos fármacos , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/genética , Estudos Transversais , Citocromo P-450 CYP2C19/metabolismo , Diabetes Mellitus/genética , Feminino , Genótipo , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Testes de Função Plaquetária , Polimorfismo Genético , Adulto JovemRESUMO
The C/EBPE gene, located in 14q11.2, encodes for a B/zip-type transcription factor. The C/EBPÉ is involved in terminal differentiation and functional maturity of granulocyte progenitor cells and in cell apoptosis during myeloid differentiation. A C/EBPE gene has recently been described as a candidate gene involved in clinical variability of ß-thalassemia (ß-thal). In this study, the C/EBPE gene was sequenced in 146 subjects divided into the severe type of ß-thal major (ß-TM) and moderate type of ß-thal intermedia (ß-TI), and a control group. The analysis identified the rs45496295 (C > T) polymorphism in the heterozygous state in 73.9% ß-TI patients, which was not the case in the ß-TM patients or in the control group. Thus, the T allele is consequently associated with the ß-TI group (p = 10-3). According to the Human Splicing Finder (version 3.0, Marseille, France), the presence of the rs45496295 polymorphism leads the creation of a new intronic exotic splicing enhancer (ESE) site. Moreover, the T allele of rs45496295 is associated with a lower transfusion regimen (p = 10-3) and a higher pretransfusion hemoglobin (Hb) rate (p = .006). The comparison of several factors concerning T allele carriers and non-carriers showed that the T allele does not act on the Hb F rate. The T allele of rs45496295, associated with moderate type of ß-thal, seems to modify the C/EBPÉ action, thereby preventing the hemolysis.
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Proteínas Estimuladoras de Ligação a CCAAT/genética , Polimorfismo de Nucleotídeo Único , Talassemia beta/genética , Adulto , Hemoglobina Fetal/metabolismo , Hemoglobinas/metabolismo , Hemólise/genética , HumanosRESUMO
INTRODUCTION: Inherited abnormalities of fibrinogen (FG) are rare coagulation disorders divided into two types: quantitative abnormalities (afibrinogenemia and hypofibrinogenemia) or qualitative abnormalities (dysfibrinogenemia and hypo-dysfibrinogenemia) of circulating fibrinogen. In particular, congenital afibrinogenemia is inherited as an autosomal recessive mode and is usually determined by homozygous or compound heterozygous mutations affecting any of the three fibrinogen genes (FGA, FGB and FGG), resulting in the complete absence or extremely reduced amount of fibrinogen. The aim of the present study was to characterize the fibrinogen abnormalities in two Tunisian families. METHODS: Coagulation studies were performed on the patients and family members. All the exons and the flanking intron regions of fibrinogen genes were screened by direct sequencing. RESULTS: Probands had concomitant bleeding complications with infinitely prolonged standard coagulation assays. Mutational screening of the fibrinogen gene cluster of each proband, disclosed two previously undescribed homozygous point mutations. The first mutation was a major truncation (AαArg252Stop) leads to a severe premature termination codon in the exon 5 of the FGA gene. This mutation defines in vivo the importance of the αC flexible segment in the secretion of a stable fibrinogen molecule. The second afibrinogenemic mutation (BßGly295Ala) occurs in the exon 7 of the FGB gene. This missense mutation would probably lead to significant conformational change not allowing the expression of the fibrinogen protein. CONCLUSION: Current molecular characterization of these two fibrinogen abnormalities confirms the importance of the first portion of αC-region (αC-connector) as well as the Bß globular domain in the secretion processes.
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Afibrinogenemia/genética , Fibrinogênio/genética , Mutação de Sentido Incorreto , Adulto , Afibrinogenemia/sangue , Afibrinogenemia/epidemiologia , Idoso , Sequência de Aminoácidos , Sequência de Bases , Coagulação Sanguínea , Criança , Pré-Escolar , Feminino , Fibrinogênio/química , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Linhagem , Conformação Proteica , Tunísia/epidemiologia , Adulto JovemRESUMO
BACKGROUND: In this work, we are interested to study for the first time the extragenic polymorphic marker MP6d9 in cystic fibrosis and healthy cohort in Tunisia to establish the contribution of MP6d9 polymorphism in the phenotypic variability of CF patients. METHODS: Our study enrolled 112 CF patients and 100 healthy controls. The analysis of the polymorphic marker MP6d9 was performed using the PCR-RFLP technique. RESULTS: Statistical difference was found in the genotype and allelic distribution between CF patients and control groups. We found that the 2/2 genotype was higher in CF patients than in controls (58.9% vs 23%). We noted that the 2/2 genotype is associated with severe clinical manifestations. CONCLUSION: Based on the above data, it seems that this genotype has led to the deterioration of our patient's clinical manifestation. This study enabled us to understanding the involvement of the MP6d9 marker in the CF clinical expression in the Tunisian population.
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Fibrose Cística/genética , Marcadores Genéticos , Polimorfismo Genético , Adolescente , Análise do Polimorfismo de Comprimento de Fragmentos Amplificados , Estudos de Casos e Controles , Criança , Pré-Escolar , Fibrose Cística/diagnóstico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Projetos Piloto , Polimorfismo de Fragmento de Restrição , Índice de Gravidade de Doença , TunísiaRESUMO
The identification of polymorphism A4059V associated with the 12276 A>G at exon 45 of the PKD1 gene in a Tunisian polycystic patient.
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Rim Policístico Autossômico Dominante/genética , Rim Policístico Autossômico Dominante/patologia , Polimorfismo de Nucleotídeo Único , Canais de Cátion TRPP/genética , Sequência de Bases , Humanos , Masculino , Pessoa de Meia-Idade , TunísiaAssuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/diagnóstico , Mutação da Fase de Leitura , Sequência de Bases , Estudos de Casos e Controles , Fibrose Cística/genética , Feminino , Estudos de Associação Genética , Aconselhamento Genético , Humanos , Lactente , Técnicas de Diagnóstico Molecular , Dados de Sequência Molecular , Linhagem , Análise de Sequência de DNA , Deleção de Sequência , TunísiaRESUMO
BACKGROUND AND OBJECTIVES: Analbuminemia is a very rare autosomal recessive disorder. It is an allelic heterogeneous defect caused by a variety of mutations within the albumin gene. We describe in this report two new cases of analbuminemia in Libyans. DESIGN AND METHODS: The 14 coding exons of the human serum albumin (HSA) gene and their intron-exon junctions were PCR amplified. The products were screened for mutations by Denaturing High Performance Liquid Chromatography (DHPLC). Samples with altered DHPLC profiles were sequenced. RESULTS: DNA sequencing revealed the presence of a novol homozygous GâT transition in the first base of intron 11 (c.1428+1G>T), in both children. This mutation destroys the GT consensus donor sequence found at the 5' end of most intervening sequences and would cause the defective pre-mRNA splicing. CONCLUSION: Molecular diagnosis based on DHPLC and DNA sequencing represents a powerful tool to study molecular defects causing analbuminemia.
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Hipoalbuminemia/genética , Albumina Sérica/deficiência , Albumina Sérica/genética , Sequência de Bases , Pré-Escolar , Análise Mutacional de DNA , Estudos de Associação Genética , Heterozigoto , Humanos , Lactente , Líbia , Masculino , Dados de Sequência Molecular , Sítios de Splice de RNARESUMO
Hereditary persistence of fetal hemoglobin (HPFH) is a group of genetically heterogeneous conditions characterized by continued expression of fetal hemoglobin (HbF) in adulthood. HPFH may be due not only to point mutations or large deletions in different regions of the cluster ß globin, but also to variations in several polymorphic sequences in this cluster. The objective of this work was to evaluate effects of polymorphic markers within cluster ß globin on HbF expression. For the purpose, we have explored in this first study of Tunisian HPFH four polymorphic regions of ß globin cluster in 68 healthy adults (34 subjects with high levels of HbF and 34 with normal HbF levels). Our results showed that the increase of HbF levels is associated with the -158 Gγ C â T polymorphism, the TG(18)CG(2)CACG, TC TG(9)AG TG(2)CG(2) and TG(11)CG(4) configurations in the second intron of Gγ gene and the -540 ß (AT)(6)T(9) and (AT)(7)T(8) repeated sequences. Among the 34 subjects with raised levels of HbF, approximately 97% carried one or more of these six markers. This study suggests that there is a significant association between certain polymorphic configurations of the ß globin cluster and the increase of HbF levels in healthy individuals.
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Hemoglobina Fetal/metabolismo , Família Multigênica/genética , Polimorfismo Genético , Globinas beta/genética , Adolescente , Adulto , Alelos , Feminino , Frequência do Gene/genética , Marcadores Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Motivos de Nucleotídeos/genética , Fenótipo , Regiões Promotoras Genéticas/genética , Análise de Sequência de DNA , Adulto JovemRESUMO
BACKGROUND: There are few data on the molecular basis of Cystic Fibrosis (CF) in North Africa, probably due to under-diagnosis. AIM: This is the first study of cystic fibrosis transmembrane conductance regulator (CFTR) mutations in the Libyan population. SUBJECTS AND METHODS: This study analysed the complete coding region and flanking intronic sequences of the CFTR gene in 10 unrelated Libyan CF patients. RESULTS: This study identified four mutations (F508del, c.1670delC, N1303K and E1104X), with a high frequency of the latter. CONCLUSION: Identification of CF mutations facilitates molecular investigation of cystic fibrosis in the Libyan population and helps to provide effective genetic counselling among CF families.