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BACKGROUND: Primary carnitine deficiency (PCD) denotes low carnitine levels with an autosomal recessive pattern of inheritance. Cardiomyopathy is the most common cardiac symptom in patients with PCD, and early diagnosis can prevent complications. Next-generation sequencing can identify genetic variants attributable to PCD efficiently. OBJECTIVE: We aimed to detect the genetic cause of the early manifestations of hypertrophic cardiomyopathy and metabolic abnormalities in an Iranian family. METHODS: We herein describe an 8-year-old boy with symptoms of weakness and lethargy diagnosed with PCD through clinical evaluations, lab tests, echocardiography, and cardiac magnetic resonance imaging. The candidate variant was confirmed through whole-exome sequencing, polymerase chain reaction, and direct Sanger sequencing. The binding efficacy of normal and mutant protein-ligand complexes were evaluated via structural modeling and docking studies. RESULTS: Clinical evaluations, echocardiography, and cardiac magnetic resonance imaging findings revealed hypertrophic cardiomyopathy as a clinical presentation of PCD. Whole-exome sequencing identified a new homozygous variant, SLC22A5 (NM_003060.4), c.821G > A: p.Trp274Ter, associated with carnitine transport. Docking analysis highlighted the impact of the variant on carnitine transport, further indicating its potential role in PCD development. CONCLUSIONS: The c.821G > A: p.Trp274Ter variant in SLC22A5 potentially acted as a pathogenic factor by reducing the binding affinity of organic carnitine transporter type 2 proteins for carnitine. So, the c.821G > A variant may be associated with carnitine deficiency, metabolic abnormalities, and cardiomyopathic characteristics.
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Cardiomiopatias , Cardiomiopatia Hipertrófica , Hiperamonemia , Doenças Musculares , Masculino , Humanos , Criança , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Carnitina/genética , Carnitina/metabolismo , Irã (Geográfico) , Membro 5 da Família 22 de Carreadores de Soluto/genética , Hiperamonemia/diagnóstico , Hiperamonemia/genética , Hiperamonemia/complicações , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/genética , Cardiomiopatia Hipertrófica/complicações , MutaçãoRESUMO
Cardiovascular diseases (CVDs) constitute one of the significant causes of death worldwide. Different pathological states are linked to CVDs, which despite interventions and treatments, still have poor prognoses. The genetic component, as a beneficial tool in the risk stratification of CVD development, plays a role in the pathogenesis of this group of diseases. The emergence of genome-wide association studies (GWAS) have led to the identification of non-coding parts associated with cardiovascular traits and disorders. Variants located in functional non-coding regions, including promoters/enhancers, introns, miRNAs and 5'/3' UTRs, account for 90% of all identified single-nucleotide polymorphisms associated with CVDs. Here, for the first time, we conducted a comprehensive review on the reported non-coding variants for different CVDs, including hypercholesterolemia, cardiomyopathies, congenital heart diseases, thoracic aortic aneurysms/dissections and coronary artery diseases. Additionally, we present the most commonly reported genes involved in each CVD. In total, 1469 non-coding variants constitute most reports on familial hypercholesterolemia, hypertrophic cardiomyopathy and dilated cardiomyopathy. The application and identification of non-coding variants are beneficial for the genetic diagnosis and better therapeutic management of CVDs.
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Doenças Cardiovasculares , MicroRNAs , Humanos , Doenças Cardiovasculares/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Fenótipo , MicroRNAs/genéticaRESUMO
BACKGROUND: The MYH7 gene, which encodes the slow/ß-cardiac myosin heavy chain, is mutated in myosin storage myopathy (MSM). The clinical spectrum of MSM is quite heterogeneous in that it ranges from cardiomyopathies to skeletal myopathies or a combination of both, depending on the affected region. In this study, we performed clinical and molecular examinations of the proband of an Iranian family with MSM in an autosomal dominant condition exhibiting proximal muscle weakness and dilated cardiomyopathy. METHODS: Following thorough clinical and paraclinical examinations, whole-exome sequencing `was performed on the proband (II-5). Pathogenicity prediction of the candidate variant was performed through in-silico analysis. Co-segregation analysis of the WES data among the family members was carried out by PCR-based Sanger sequencing. RESULTS: A novel heterozygous missense variant, MYH7 (NM_000257): c.C1888A: p.Pro630Thr, was found in the DNA of the proband and his children and confirmed by Sanger sequencing. The in-silico analysis revealed that p.Pro630Thr substitution was deleterious. The novel sequence variant fell within a highly conserved region of the head domain. Our findings expand the spectrum of MYH7 mutations. CONCLUSIONS: This finding could improve genetic counseling and prenatal diagnosis in families with clinical manifestations associated with MYH7-related myopathy.
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Cardiomiopatia Dilatada , Doenças Musculares , Criança , Humanos , Músculo Esquelético , Cardiomiopatia Dilatada/diagnóstico por imagem , Cardiomiopatia Dilatada/genética , Irã (Geográfico) , Mutação , Cadeias Pesadas de Miosina/genética , Linhagem , Miosinas Cardíacas/genéticaRESUMO
BACKGROUND: Salih myopathy, characterised by both congenital myopathy and fatal dilated cardiomyopathy, is an inherited muscle disorder that affects skeletal and cardiac muscles. TTN has been identified as the main cause of this myopathy, the enormous size of this gene poses a formidable challenge to molecular genetic diagnostics. METHOD: In the present study, whole-exome sequencing, cardiac MRI, and metabolic parameter assessment were performed to investigate the genetic causes of Salih myopathy in a consanguineous Iranian family who presented with titinopathy involving both skeletal and heart muscles in an autosomal recessive inheritance pattern. RESULTS: Two missense variants of TTN gene (NM_001267550.2), namely c.61280A>C (p. Gln20427Pro) and c.54970G>A (p. Gly18324Ser), were detected and segregations were confirmed by polymerase chain reaction-based Sanger sequencing. CONCLUSIONS: The compound heterozygous variants, c.61280A>C, (p. Gln20427Pro) and c.54970G>A, (p. Gly18324Ser) in the TTN gene appear to be the cause of Salih myopathy and dilated cardiomyopathy in the family presented. Whole-exome sequencing is an effective molecular diagnostic tool to identify the causative genetic variants of large genes such as TTN.
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A major problem of hemophilia A (HA) treatment is the development of factor VIII (FVIII) inhibitor, which usually occurs shortly after initiating replacement therapy. Several studies showed the correlation between inhibitor development and polymorphisms in inflammatory and immune response genes of HA patients; however, literature data are not available to prove this association in Iranian population. The aim of this study was to investigate a possible association between FVIII inhibitor formation and the polymorphisms of 16 inflammatory and immune response genes in Iranian severe HA patients (FVIII activity < 1%). This case-control study was performed on 55 patients with severe HA inhibitors and 45 samples without inhibitors from Iranian Comprehensive Hemophilia Care center. After extraction of whole genomic DNA from blood samples and design of primers for 16 genes, the genotyping was performed by Tetra primer ARMS PCR, and the validation of single nucleotide polymorphisms was determined by DNA sequencing. The data indicated that there was a significant association between inhibitor development, and F13A1 (TT), DOCK2 (CC& CT), and MAPK9 (TT) genotypes. Moreover, a considerably increased inhibitor risk carrying T, C, and T allele for F13A1, DOCK2, and MAPK9 genes was observed in patients with inhibitors, respectively. In contrast, there was no statistically significant difference between the genotypic and allelic frequencies for other genes in patients with inhibitors compared to patients without inhibitors. These results demonstrate that only polymorphisms in F13A1, DOCK2, and MAPK9 genes are associated with the risk of developing FVIII inhibitors in Iranian HA patients.
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Alelos , Inibidores dos Fatores de Coagulação Sanguínea/genética , Frequência do Gene , Fatores de Troca do Nucleotídeo Guanina/genética , Hemofilia A/genética , Proteína Quinase 9 Ativada por Mitógeno/genética , Polimorfismo Genético , Adulto , Fator VIII/genética , Proteínas Ativadoras de GTPase , Humanos , Irã (Geográfico) , MasculinoRESUMO
The association of Merkel cell polyomavirus (MCPyV) with Merkel cell carcinoma (MCC) in immunocompromised individuals has been revealed in a number of surveys. The study of MCPyV specific antibody titers and viral loads in such patients has a great attraction for research groups interested in viral reactivation. In this cross-sectional study to evaluate MCPyV antibody titer, DNA prevalence and viral load in peripheral blood mononuclear cells (PBMCs), we examined 205 HIV-1 infected patients and 100 un-infected controls. The HIV-1 infected patients divided into two groups (HIV/AIDS and non-AIDS) according to their CD4 status. Total IgG antibody titer against MCPyV was analyzed by virus like particle (VLP)-based enzyme linked immunosorbent assay (ELISA). Presence of MCPyV-DNA in subject's PBMCs was examined by quantitative real-time PCR assay. Levels of anti-MCPyV IgG in HIV/AIDS patients were significantly higher than those in non-AIDS HIV-infected and control subjects (p value = <0.001). The prevalence rate of MCPyV-DNA in PBMCs of HIV/AIDS, non-AIDS HIV-infected and un-infected controls were 17%, 16%, and 14% respectively. The MCPyV viral load among the groups ranged between 0.15 to 2.9 copies/103cells (median, 1.9 copies/103cells), with no significant difference between the studied populations (p value = 0.3).
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Síndrome da Imunodeficiência Adquirida/sangue , Síndrome da Imunodeficiência Adquirida/patologia , Anticorpos Antivirais/sangue , Carcinoma de Célula de Merkel/sangue , Imunoglobulina G/sangue , Poliomavírus das Células de Merkel/imunologia , Síndrome da Imunodeficiência Adquirida/imunologia , Adulto , Anticorpos Antivirais/imunologia , Carcinoma de Célula de Merkel/imunologia , Carcinoma de Célula de Merkel/patologia , Carcinoma de Célula de Merkel/virologia , Estudos Transversais , Progressão da Doença , Feminino , HIV-1/genética , HIV-1/imunologia , HIV-1/fisiologia , Humanos , Imunoglobulina G/imunologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/virologia , Masculino , Poliomavírus das Células de Merkel/genética , Poliomavírus das Células de Merkel/fisiologia , Carga Viral , Adulto JovemRESUMO
BACKGROUND: Long QT syndrome (LQTS) is a cardiac channelopathy characterized by impaired myocardial repolarization that predisposes to life-threatening arrhythmias. This study aimed to elucidate the genetic basis of LQTS in an affected Iranian family using whole exome sequencing (WES). METHODS: A 37-year-old woman with a personal and family history of sudden cardiac arrest and LQTS was referred for genetic study after losing her teenage daughter due to sudden cardiac death (SCD). WES was performed and variants were filtered and prioritized based on quality, allele frequency, pathogenicity predictions, and conservation scores. Sanger sequencing confirmed segregation in the family. RESULTS: WES identified a novel heterozygous frameshift variant (NM_000238.4:c.3257_3258insG; pGly1087Trpfs*32) in the KCNH2 encoding the α-subunit of the rapid delayed rectifier potassium channel responsible for cardiac repolarization. This variant, predicted to cause a truncated protein, is located in the C-terminal region of the channel and was classified as likely pathogenic based on ACMG guidelines. The variant was absent in population databases and unaffected family members. CONCLUSION: This study reports a novel KCNH2 frameshift variant in an Iranian family with LQTS, expanding the spectrum of disease-causing variants in this gene. Our findings highlight the importance of the C-terminal region in KCNH2 for proper channel function and the utility of WES in identifying rare variants in genetically heterogeneous disorders like LQTS. Functional characterization of this variant is warranted to fully elucidate its pathogenic mechanisms and inform personalized management strategies.
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Canal de Potássio ERG1 , Sequenciamento do Exoma , Síndrome do QT Longo , Linhagem , Humanos , Síndrome do QT Longo/genética , Canal de Potássio ERG1/genética , Feminino , Adulto , Mutação da Fase de LeituraRESUMO
OBJECTIVE: We studied the clinical and molecular features of a family with hypertrophic cardiomyopathy (HCM). BACKGROUND: A very heterogeneous disease affecting the heart muscle, HCM is mostly caused by variants in the proteins of sarcomeres. The detection of HCM pathogenic variants can affect the handling of patients and their families. METHODS: Whole-exome sequencing (WES) was performed to assess the genetic cause(s) of HCM in a consanguineous Iranian family. RESULTS: Missense likely pathogenic variant c.1279C>T (p.Arg427Cys) within exon 7 of the LMNA gene (NM_170707) was found. The segregations were confirmed by polymerase chain reaction-based Sanger sequencing. CONCLUSIONS: Variant c.1279C>T (p.Arg427Cys) in the LMNA gene seemed to have been the cause of HCM in the family. A few LMNA gene variants related to HCM phenotypes have been recognized so far. Identifying HCM genetic basis confers significant opportunities to understand how the disease can develop and, by extension, how this progression can be arrested. Our study supports WES effectiveness for first-tier variant screening of HCM in a clinical setting.
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Cardiomiopatia Hipertrófica , Humanos , Sequenciamento do Exoma , Irã (Geográfico) , Linhagem , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/patologia , Fenótipo , Mutação , Lamina Tipo A/genéticaRESUMO
The giant protein titin (TTN) is a sarcomeric protein that forms the myofibrillar backbone for the components of the contractile machinery which plays a crucial role in muscle disorders and cardiomyopathies. Diagnosing TTN pathogenic variants has important implications for patient management and genetic counseling. Genetic testing for TTN variants can help identify individuals at risk for developing cardiomyopathies, allowing for early intervention and personalized treatment strategies. Furthermore, identifying TTN variants can inform prognosis and guide therapeutic decisions. Deciphering the intricate genotype-phenotype correlations between TTN variants and their pathologic traits in cardiomyopathies is imperative for gene-based diagnosis, risk assessment, and personalized clinical management. With the increasing use of next-generation sequencing (NGS), a high number of variants in the TTN gene have been detected in patients with cardiomyopathies. However, not all TTN variants detected in cardiomyopathy cohorts can be assumed to be disease-causing. The interpretation of TTN variants remains challenging due to high background population variation. This narrative review aimed to comprehensively summarize current evidence on TTN variants identified in published cardiomyopathy studies and determine which specific variants are likely pathogenic contributors to cardiomyopathy development.
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Cardiomiopatias , Humanos , Conectina/genética , Cardiomiopatias/genética , Intervenção Educacional Precoce , Aconselhamento Genético , Testes GenéticosRESUMO
Introduction: Coronary artery disease (CAD) is the leading health complication worldwide because of its high prevalence and mortality. The association between CAD susceptibility and the rs599839 (C/T) polymorphism in the human proline and serine-rich coiled-coil (PSRC1) was reported in a genome-wide association study. To validate this association, we performed this case-control study to genotype the 1p13.3 (rs599839) locus in a sample of the Iranian population with CAD (stenosis≥70% in≥1 coronary artery). Methods: We performed an association analysis with PCR and Sanger sequencing of rs599839 (C/T) polymorphism and CAD risk in 280 CAD patients and 287 healthy controls defined as a coronary calcium score of zero and no noncalcified plaques in coronary computed tomography angiography. SPSS, version 16.0, was applied for statistical analysis. Results: The rs599839 (C/T) locus showed a significant association with CAD (P value<0.001). TT and CT genotypes were associated with CAD (P value<0.001). Furthermore, the dominant status (TT+CT vs. CC) was associated with an increased risk of CAD (OR, 9.14; 95% CI, 3.77 to 22.15; and P value<0.001). Conclusion: The study findings indicate strong evidence for rs599839 (C/T) association with CAD risk.
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BACKGROUND: Alexander disease (AxD) is a rare leukodystrophy with an autosomal dominant inheritance mode. Variants in GFAP lead to this disorder and it is classified into three distinguishable subgroups: infantile, juvenile, and adult-onset types. OBJECTIVE: The aim of this study is to report a novel variant causing AxD and collect all the associated variants with juvenile and adult-onset as well. METHODS: We report a 2-year-old female with infantile AxD. All relevant clinical and genetic data were evaluated. Search strategy for all AxD types was performed on PubMed. The extracted data include total recruited patients, number of patients carrying a GFAP variant, nucleotide and protein change, zygosity and all the clinical symptoms. RESULTS: A novel de novo variant c.217A > G: p. Met73Val was found in our case by whole-exome sequencing. In silico analysis categorized this variant as pathogenic. Totally 377 patients clinically diagnosed with juvenile or adult-onset forms were recruited in these articles, among them 212 patients were affected with juvenile or adult-onset form carrier of an alteration in GFAP. A total of 98 variants were collected. Among these variants c.262C > T 11/212 (5.18%), c.1246C > T 9/212 (4.24%), c.827G > T 8/212 (3.77%), c.232G > A 6/212 (2.83%) account for the majority of reported variants. CONCLUSION: This study highlighted the role of genetic in AxD diagnosing. It also helps to provide more information in order to expand the genetic spectrum of Iranian patients with AxD. Our literature review is beneficial in defining a better genotype-phenotype correlation of AxD disorder.
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Doença de Alexander , Doença de Alexander/diagnóstico , Doença de Alexander/genética , Doença de Alexander/patologia , Feminino , Proteína Glial Fibrilar Ácida/genética , Humanos , Irã (Geográfico) , Sequenciamento do ExomaRESUMO
BACKGROUND: Congenital heart defects (CHDs) are the most common congenital malformations, including structural malformations in the heart and great vessels. CHD complications such as low birth weight, prematurity, pregnancy termination, mortality, and morbidity depend on the type of defect. METHODS: In the present research, genetic analyses via whole-exome sequencing (WES) was performed on 3 unrelated pedigrees with CHDs. The candidate variants were confirmed, segregated by PCR-based Sanger sequencing, and evaluated by bioinformatics analysis. RESULTS: A novel stop-gain c.C244T:p.R82X variant in the FLT4 gene, as well as a nonsynonymous c.C1403T:p.T468M variant in the PTPN11 gene, was reported by WES. FLT4 encodes a receptor tyrosine kinase involved in lymphatic development and is known as vascular endothelial growth factor 3. CONCLUSIONS: We are the first to report a novel c.C244T variant in the FLT4 gene associated with CHDs. Using WES, we also identified a nonsynonymous variant affecting protein-tyrosine phosphatase, the non-receptor type 11 (PTPN11) gene. The clinical implementation of WES can determine gene variants in diseases with high genetic and phenotypic heterogeneity like CHDs.
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Cardiopatias Congênitas , Proteína Tirosina Fosfatase não Receptora Tipo 11 , Receptor 3 de Fatores de Crescimento do Endotélio Vascular , Humanos , Cardiopatias Congênitas/genética , Linhagem , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
OBJECTIVE: Solute carrier family 19 member 2 (SLC19A2, OMIM *603941) encodes thiamine human transporter 1 (THTR-1), which contributes to bringing thiamine (vitamin B1) into cells. Mutations in SLC19A2 lead to a rare recessive genetic disorder termed thiamine-responsive megaloblastic anemia (TRMA) syndrome. METHODS: An Iranian family with TRMA was investigated by whole-exome sequencing (WES) to determine the genetic cause(s) of the disease. Accordingly, SLC19A2 genetic variants were gathered through literature analysis. RESULTS: WES recognized a known pathogenic variant, c.697Câ >â T (p. Q233X), within exon 2 of SLC19A2 (NM_006996). Subsequently, the proband's parents and sister were confirmed as heterozygous carriers of the identified variant. CONCLUSION: The diagnostic utility and affordability of WES were confirmed as the first approach for the genetic testing of TRMA to verify the diagnosis. This analysis can be used to guide future prenatal diagnoses and determine the consequences in the other family members.
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Anemia Megaloblástica , Diabetes Mellitus , Humanos , Anemia Megaloblástica/diagnóstico , Anemia Megaloblástica/genética , Anemia Megaloblástica/patologia , Diabetes Mellitus/diagnóstico , Irã (Geográfico) , Proteínas de Membrana Transportadoras/genética , Mutação , Tiamina , Sequenciamento do Exoma , Masculino , Feminino , LinhagemRESUMO
BACKGROUND: Inversion of chromosome 9 (inv[9]) is known as one of the most common structural balanced chromosomal variations. Chromosome 9 is highly susceptible to structural rearrangements, specifically to pericentric inversions. Various investigators have posited that inv(9) with different breakpoints could be the cause of several abnormal conditions in individuals, whereas others have considered it a benign variant. To our knowledge, a consensus regarding the effects of this inversion has yet to emerge. OBJECTIVE: This study aims to discuss the pathogenic/benign effects of inv(9) in all possible clinical conditions detected in the occurrence of this abnormality. METHODS: Studies on inv(9) were collected via PubMed, MalaCards, Google Scholar, and NORD, along with the search terms of inv(9), pericentric inv(9), and chromosome 9 variants. Additionally, the incidence of inv(9) and the karyotype and clinical findings of individuals reported with this variant were investigated. RESULTS: The collection of the studies reviewed shows that inv(9) is associated with various conditions such as congenital anomalies, growth retardation, infertility, recurrent pregnancy loss, and cancer. The clinical features associated with this variant in humans vary between growth stages. Further, there have been no shared clinical findings in a specific period. CONCLUSION: Although there is no conclusive evidence for the pathogenicity of this rearrangement, prenatal genetic counseling on inv(9) and further clinical and molecular studies would be helpful in chromosome 9-related problems.
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Inversão Cromossômica , Cromossomos Humanos Par 9 , Inversão Cromossômica/genética , Feminino , Humanos , GravidezRESUMO
Introduction: Congenital heart disease (CHD) is the most common congenital abnormality and the main cause of infant mortality worldwide. Some of the mutations that occur in the GATA4 gene region may result in different types of CHD. Here, we report our in silico analysis of gene variants to determine the effects of the GATA4 gene on the development of CHD. Methods: Online 1000 Genomes Project, ExAC, gnomAD, GO-ESP, TOPMed, Iranome, GME, ClinVar, and HGMD databases were drawn upon to collect information on all the reported GATA4 variations.The functional importance of the genetic variants was assessed by using SIFT, MutationTaster, CADD,PolyPhen-2, PROVEAN, and GERP prediction tools. Thereafter, network analysis of the GATA4protein via STRING, normal/mutant protein structure prediction via HOPE and I-TASSER, and phylogenetic assessment of the GATA4 sequence alignment via ClustalW were performed. Results: The most frequent variant was c.874T>C (45.58%), which was reported in Germany.Ventricular septal defect was the most frequent type of CHD. Out of all the reported variants of GATA4,38 variants were pathogenic. A high level of pathogenicity was shown for p.Gly221Arg (CADD score=31), which was further analyzed. Conclusion: The GATA4 gene plays a significant role in CHD; we, therefore, suggest that it be accorded priority in CHD genetic screening.
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OBJECTIVES: Hemophilia A (HA) is an inherited and rare X-linked bleeding disorder which is caused by mutations of the factor VIII gene (FVIII). Long non-coding RNAs (lncRNAs) are non-protein coding sequence transcripts containing more than 200 nucleotides and have potential in diagnosis, prevention and treatment of cancers and inherited bleeding disorders like thalassemia. The goal of this study was to determine the relationship between the expression of lncRNAs and the incidence of hemophilia A in Iranian population. METHODS: In this study, after bioinformatics analysis and lncRNA identification, the expression of two lncRNAs including NONHSAT139215 and NONHSAT139219 was investigated among the blood samples of severe hemophilia A and healthy (non-hemophilia) subjects using the relative qRT-PCR technique. RESULTS: The melting curve analysis confirmed the specificity of primers. Also, the standard curve showed that the efficiency of reactions for ß2-microglobulin (B2M), NONHSAT139215 and NONHSAT139219 was 1.91, 1.96 and 2.01, respectively. On the other hand, the statistical analysis using REST software indicated that the expression of NONHSAT139219 and NONHSAT139215 in severe HA patients was significantly down-regulated as compared to control group (p < .05). DISCUSSION: Our results demonstrated that a decrease in the expression of two lncRNAs located in FVIII gene may play an important role for the development of severe hemophilia A for the first time. CONCLUSIONS: Briefly, the abnormal expression levels of lncRNAs in hemophilia A cases may be correlated with disease intensity. However, further studies of these lncRNAs are required to provide a useful insight into hemophilia biology.
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Regulação da Expressão Gênica , Hemofilia A/sangue , RNA Longo não Codificante/sangue , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , HumanosRESUMO
Objectives Development of neutralizing antibodies against factor VIII is the major complication in hemophilia care which makes replacement therapies ineffective. The reports showed that inflammatory cytokines play an important role in inhibitor production. In the present study, the relationship between inhibitor development and the polymorphisms of two cytokine genes was studied in severe hemophiliac patients from Iran. Methods In this case-control study, three polymorphisms of immune regulatory genes [TGF-ß (rs1982037) and IL-2 (rs2069762, rs4833248)] were analyzed in 100 Iranian hemophilia A patients divided into 55 inhibitor positive and 45 inhibitor negative patients using Tetra primer ARMS PCR, and DNA sequencing. Results The analysis of polymorphisms in the TGF-ß and IL-2 genes showed no association between the genotypes and the production of inhibitors (p > 0.05). Also, comparison of allele frequencies for TGF-ß and IL-2 genes between two groups indicated no significant differences associated with the development of FVIII inhibitors (p > 0.05). Discussion In contrast with some reports involving the correlation between polymorphisms of the TGF-ß1 and IL-2 genes and inhibitor development in the world, no statistically significant differences in analysis of the alleles and genotypes for TGF-ß and IL-2 genes were found between the inhibitor and non-inhibitor Iranian patients. Thus, other genetic markers influencing the immune response to replacement therapy in patients with hemophilia should be identified. Conclusions Regarding our results in molecular predisposition for inhibitor development, further studies of effective genetic markers are required as a prerequisite for the development of novel immunogenic therapeutic approaches in the future.
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Inibidores dos Fatores de Coagulação Sanguínea/sangue , Hemofilia A , Interleucina-2/genética , Polimorfismo Genético , Fator de Crescimento Transformador beta1/genética , Adolescente , Adulto , Inibidores dos Fatores de Coagulação Sanguínea/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Hemofilia A/sangue , Hemofilia A/genética , Humanos , Interleucina-2/sangue , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Fator de Crescimento Transformador beta1/sangueRESUMO
INTRODUCTION: The development of an effective therapeutic vaccine to induce cancer-specific immunity remains problematic. Recently, a species of intracellular pathogen known as Listeria monocytogenes (Lm) has been used to transfer DNA, RNA and proteins into tumour cells as well as elicit an immune response against tumour-specific antigens. Areas covered: Herein, the authors provide the mechanisms of different Listeria monocytogenes strains, which are potential therapeutic cancer vaccine vectors, in addition to their preclinical and clinical development. They also speculate on the future of Lm-based tumour immunotherapies. The article is based on literature published on PubMed and data reported in clinical trials. Expert opinion: Attenuated strains of Listeria monocytogenes have safely been applied as therapeutic bacterial vectors for the delivery of cancer vaccines. These vectors stimulate MHCI and MHCII pathways as well as the proliferation of antigen-specific T lymphocytes. Several preclinical studies have demonstrated the potency of Lm in intracellular gene and protein delivery in vitro and in vivo. They have also indicated safety and efficiacy in clinical trials. Readers should be aware that the ability of attenuated Lm strains to induce potent immune responses depends on the type of deleted or inactivated Lm virulent gene or genes.
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Vacinas Anticâncer/imunologia , Listeria monocytogenes/imunologia , Neoplasias/terapia , Animais , Linfócitos T CD8-Positivos/imunologia , Ensaios Clínicos como Assunto , Imunoterapia , Neoplasias/imunologiaRESUMO
INTRODUCTION: Alport Syndrome has a prevalence of 1 case per 5,000 people and 85% of patients have the X-linked form, where affected males develop renal failure and usually have high-tone sensorineural deafness by age 20. The main abnormality is deficient synthesis of type IV collagen, the main component of basement membranes. Common ocular abnormalities of this syndrome consist of dot-and-fleck retinopathy, posterior polymorphous corneal dystrophy, and anterior lenticonus, but other ocular defects such as cataracts, posterior lenticonus, and retinal detachments have also been reported. CASE PRESENTATION: We report two cases of anterior lenticonus due to Alport Syndrome and describe clear lens phacoemulsification and foldable intraocular lens implantation as an effective and safe refractive procedure in the four eyes of these two patients. CONCLUSION: All four eyes of the two patients were in good condition after surgery and achieved satisfactory optical and visual results and had no remarkable complications at six-months follow-up. Clear lens phacoemulsification with foldable intraocular lens implantation can be used as an efficient and safe procedure for vision disorders in these patients.