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In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated with torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with AMC5-TOR1A have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with foetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71%, with higher mortality in males. Death occurred at a median age of 1.2 months (1 week-9 years), due to respiratory failure, cardiac arrest or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival.
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Distonia , Distúrbios Distônicos , Malformações do Sistema Nervoso , Masculino , Humanos , Estudos Transversais , Mutação/genética , Fenótipo , Distonia/genética , Distúrbios Distônicos/genética , Chaperonas Moleculares/genéticaRESUMO
PURPOSE: Brain monoamine vesicular transport disease is an infantile-onset movement disorder that mimics cerebral palsy. In 2013, the homozygous SLC18A2 variant, p.Pro387Leu, was first reported as a cause of this rare disorder, and dopamine agonists were efficient for treating affected individuals from a single large family. To date, only 6 variants have been reported. In this study, we evaluated genotype-phenotype correlations in individuals with biallelic SLC18A2 variants. METHODS: A total of 42 affected individuals with homozygous SLC18A2 variant alleles were identified. We evaluated genotype-phenotype correlations and the missense variants in the affected individuals based on the structural modeling of rat VMAT2 encoded by Slc18a2, with cytoplasm- and lumen-facing conformations. A Caenorhabditis elegans model was created for functional studies. RESULTS: A total of 19 homozygous SLC18A2 variants, including 3 recurrent variants, were identified using exome sequencing. The affected individuals typically showed global developmental delay, hypotonia, dystonia, oculogyric crisis, and autonomic nervous system involvement (temperature dysregulation/sweating, hypersalivation, and gastrointestinal dysmotility). Among the 58 affected individuals described to date, 16 (28%) died before the age of 13 years. Of the 17 patients with p.Pro237His, 9 died, whereas all 14 patients with p.Pro387Leu survived. Although a dopamine agonist mildly improved the disease symptoms in 18 of 21 patients (86%), some affected individuals with p.Ile43Phe and p.Pro387Leu showed milder phenotypes and presented prolonged survival even without treatment. The C. elegans model showed behavioral abnormalities. CONCLUSION: These data expand the phenotypic and genotypic spectra of SLC18A2-related disorders.
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Encefalopatias , Distonia , Transtornos dos Movimentos , Humanos , Animais , Ratos , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas Vesiculares de Transporte de Monoamina/genética , Proteínas Vesiculares de Transporte de Monoamina/metabolismo , Transtornos dos Movimentos/genética , Aminas , Encéfalo/metabolismoRESUMO
Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson's disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function.
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Ataxia Cerebelar/genética , Predisposição Genética para Doença/genética , Transtornos do Neurodesenvolvimento/genética , Transporte Proteico/genética , Proteínas de Transporte Vesicular/genética , Adolescente , Adulto , Animais , Criança , Pré-Escolar , Feminino , Variação Genética , Humanos , Masculino , Linhagem , Adulto Jovem , Peixe-ZebraRESUMO
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, yet the genetic cause of up to 50% of cases remains unknown. Here, we show that mutations in KLHL24 cause HCM in humans. Using genome-wide linkage analysis and exome sequencing, we identified homozygous mutations in KLHL24 in two consanguineous families with HCM. Of the 11 young affected adults identified, 3 died suddenly and 1 had a cardiac transplant due to heart failure. KLHL24 is a member of the Kelch-like protein family, which acts as substrate-specific adaptors to Cullin E3 ubiquitin ligases. Endomyocardial and skeletal muscle biopsies from affected individuals of both families demonstrated characteristic alterations, including accumulation of desmin intermediate filaments. Knock-down of the zebrafish homologue klhl24a results in heart defects similar to that described for other HCM-linked genes providing additional support for KLHL24 as a HCM-associated gene. Our findings reveal a crucial role for KLHL24 in cardiac development and function.
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Arritmias Cardíacas/genética , Cardiomiopatia Hipertrófica/mortalidade , Insuficiência Cardíaca/genética , Proteínas Repressoras/genética , Adulto , Animais , Arritmias Cardíacas/mortalidade , Arritmias Cardíacas/fisiopatologia , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/patologia , Morte Súbita Cardíaca/patologia , Desmina/genética , Modelos Animais de Doenças , Feminino , Ligação Genética/genética , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Homozigoto , Humanos , Masculino , Mutação , Linhagem , Fenótipo , Peixe-Zebra/genéticaRESUMO
Cardiovascular diseases (CVDs) are one of the leading causes of morbidity and mortality. Standard therapies have failed to significantly increase patients' survival. Moreover, the majority of conventional screening procedures are ineffective for the diagnosis of CVDs at early stages. Accumulating evidence suggests that numerous cell types release a class of nano-sized vesicles named exosomes into the extracellular space. Exosomes are widely distributed in various body fluids and contain a number of diverse biomolecules such as proteins, lipids, and both mRNA and noncoding RNAs which reflect host-cell molecular architecture. MicroRNAs (miRNAs), which can be found in exosomes, could be taken up by both neighboring and distal cells. Not only has recent evidence indicated the regulatory role of exosomal miRNAs in the pathogenesis of CVD, but it has also been shown that differential expression of exosomal miRNAs in CVDs has made them promising biomarkers for early detection of CVDs. Owing to these remarkable features, exosomal miRNAs have emerged as hot spots in research. This review summarizes the role of exosomal miRNAs in the pathogenesis of CVDs and discusses their potential application in the clinical setting as both therapeutic and diagnostic tools.
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Doenças Cardiovasculares/genética , Exossomos/genética , MicroRNAs/genética , RNA não Traduzido/genética , Biomarcadores/análise , Humanos , RNA Mensageiro/genéticaRESUMO
BACKGROUND: The relationship between thrombophilia genes and recurrent pregnancy loss has been discussed. The aim of this study was to investigate the association between of MTHFR C677T, A1298C, F2G20210A, and F5 G1691A genetic variants among Iranian women with recurrent miscarriage. METHODS: A total of 245 women with two or more recurrent pregnancy loss, with mean age years were enrolled in the study. To compare genotypes, we have selected 250 healthy women without history of miscarriage as control group. Genomic DNA of participants was evaluated using polymerase chain reaction followed by Sanger sequencing to determine the genotype frequency. RESULTS: The mean age were 32.16 ± (21-42) and 31.81 ± (19-40) for case and control groups respectively. MTHFR C677T and A1298C mutant alleles were found to be significantly more prevalent in patients than control. However, F2G20210A and F5 G1691A genetic variants showed no significance. CONCLUSION: The allele frequencies for the assessed genotypes in this study are consistent with the data obtained for other countries. We observed significant susceptible effects of MTHFR C677T, and A1298C among participants. According to the relatively high prevalence of these variants, we recommend genetic testing for women with RPL before therapeutic decisions.
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Aborto Habitual/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Mutação/genética , Trombofilia/genética , Aborto Habitual/epidemiologia , Adulto , Alelos , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Irã (Geográfico) , Reação em Cadeia da Polimerase , Polimorfismo Genético , Gravidez , Trombofilia/complicaçõesRESUMO
BACKGROUND: IARS2 encodes a mitochondrial isoleucyl-tRNA synthetase, a highly conserved nuclear-encoded enzyme required for the charging of tRNAs with their cognate amino acid for translation. Recently, pathogenic IARS2 variants have been identified in a number of patients presenting broad clinical phenotypes with autosomal recessive inheritance. These phenotypes range from Leigh and West syndrome to a new syndrome abbreviated CAGSSS that is characterised by cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, as well as cataract with no additional anomalies. METHODS: Genomic DNA from Iranian probands from two families with consanguineous parental background and overlapping CAGSSS features were subjected to exome sequencing and bioinformatics analysis. RESULTS: Exome sequencing and data analysis revealed a novel homozygous missense variant (c.2625C > T, p.Pro909Ser, NM_018060.3) within a 14.3 Mb run of homozygosity in proband 1 and a novel homozygous missense variant (c.2282A > G, p.His761Arg) residing in an ~ 8 Mb region of homozygosity in a proband of the second family. Patient-derived fibroblasts from proband 1 showed normal respiratory chain enzyme activity, as well as unchanged oxidative phosphorylation protein subunits and IARS2 levels. Homology modelling of the known and novel amino acid residue substitutions in IARS2 provided insight into the possible consequence of these variants on function and structure of the protein. CONCLUSIONS: This study further expands the phenotypic spectrum of IARS2 pathogenic variants to include two patients (patients 2 and 3) with cataract and skeletal dysplasia and no other features of CAGSSS to the possible presentation of the defects in IARS2. Additionally, this study suggests that adult patients with CAGSSS may manifest central adrenal insufficiency and type II esophageal achalasia and proposes that a variable sensorineural hearing loss onset, proportionate short stature, polyneuropathy, and mild dysmorphic features are possible, as seen in patient 1. Our findings support that even though biallelic IARS2 pathogenic variants can result in a distinctive, clinically recognisable phenotype in humans, it can also show a wide range of clinical presentation from severe pediatric neurological disorders of Leigh and West syndrome to both non-syndromic cataract and cataract accompanied by skeletal dysplasia.
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Doenças do Desenvolvimento Ósseo/genética , Catarata/genética , Perda Auditiva Neurossensorial/genética , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Isoleucina-tRNA Ligase/genética , Doença de Leigh/genética , Doenças Mitocondriais/genética , Adulto , Sequência de Aminoácidos , Doenças do Desenvolvimento Ósseo/diagnóstico , Doenças do Desenvolvimento Ósseo/patologia , Catarata/diagnóstico , Catarata/patologia , Consanguinidade , Feminino , Expressão Gênica , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/patologia , Neuropatias Hereditárias Sensoriais e Autônomas/diagnóstico , Neuropatias Hereditárias Sensoriais e Autônomas/patologia , Homozigoto , Humanos , Doença de Leigh/diagnóstico , Doença de Leigh/patologia , Masculino , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/patologia , Modelos Moleculares , Mutação de Sentido Incorreto , Linhagem , Conformação Proteica , Subunidades Proteicas/genética , Síndrome , Sequenciamento do ExomaRESUMO
BACKGROUND: We aimed to determine the contribution of four DFNB loci and mutation analysis of gap junction beta-2 (GJB2) and GJB4 genes in autosomal recessive nonsyndromic hearing loss (ARNSHL) in South of Iran. MATERIALS AND METHODS: A total of 36 large ARNSHL pedigrees with at least two affected subjects were enrolled in the current study. The GJB2 and GJB4 genes mutations were screened using direct sequencing method. The GJB2 and GJB4 negative families were analyzed for the linkage to DFNB21, DFNB24, DFNB29, and DFNB42 loci by genotyping the corresponding STR markers using polymerase chain reaction-PAGE method. RESULTS: We found a homozygous nonsense mutation W77X and a homozygous missense mutation C169W in 5.55% of studied families in GJB2 and GJB4 genes, respectively. Five heterozygous mutations including V63G, A78T, and R127H in GJB2 gene, and R103C and R227W in GJB4 gene were detected. We identified two novel variations V63G in GJB2 and R227W in GJB4. In silico analysis predicted that both novel variations are deleterious mutations. We did not unveil any linkage between DFNB21, DFNB24, DFNB29, and DFNB42 loci and ARNSHL among studied families. CONCLUSION: This is the first report of GJB2 and GJB4 mutations from Hormozgan population. According to the previous publications regarding GJB2 and GJB4 mutations, the distribution of the mutations is different from other parts of Iran that should be considered in primary health-care programs. Further investigations are needed to evaluate the contribution of other loci in ARNSHL subjects in South of Iran.
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Spinal muscular atrophy (SMA) with progressive myoclonic epilepsy (PME) affects the nervous system. Symptoms appear in early childhood and include muscle weakness, difficulty walking, seizures, and cognitive decline. Despite introducing various therapies to restore acid ceramidase function or reduce ceramide accumulation and gene therapy to correct genetic mutations, there are still unknown underlying molecular mechanisms related to this disorder. This article reports a novel variant c.118G>C in the ASAH1 gene. The patient presented with clinical manifestations such as progressive muscle weakness and myoclonic convulsions. Clinical features and electrophysiological investigations revealed a motor neuron disease and generalized epileptic discharge. A significant temporal interval was observed between the initial diagnosis of SMA and the subsequent manifestation of myoclonic seizures. The proband was genetically assessed through whole exome sequencing (WES) followed by variant confirmation and bioinformatics analysis. According to this article's findings and previous research, further diagnostic testing and management are needed to determine the severity and progression of the patient's condition.
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Background: Plectinopathy-associated disorders are caused by mutations in the PLECTIN (PLEC) gene encoding Plectin protein. PLEC mutations cause a spectrum of diseases defined by varying degrees of signs, mostly with epidermolysis bullosa simplex with muscular dystrophy (EBS-MD) and plectinopathy-related disorder is limb-girdle muscular dystrophy type 2Q (LGMD2Q). Here we report three cases with EBS-MD and LGMD2Q disorders analyzed by exome sequencing followed by mutation confirmation. Methods: A complete clinical examination was done by expert specialists and clinical geneticists in Next Generation Genetic polyclinic, Mashhad, Iran (NGC, years 2020_2021),. Genomic DNA was extracted and evaluated through whole-exome sequencing analysis followed by Sanger sequencing for co-segregation analysis of PLEC candidate variants. Results: We found three cases with the plectinopathy-related disease, two patients with limb-girdle muscular dystrophy type 2Q (LGMD2Q), and the other affected proband suffers from epidermolysis bullosa simplex combined with muscular dystrophy (EBS-MD) with variable zygosity mutations for PLEC. Motor development disorder and muscular dystrophy symptoms have different age onset in affected individuals. Patients with EBS demonstrated symptoms such as blistering, skin scars, neonatal-onset, and nail dystrophy. Conclusion: We report plectinopathy-associated disorders to expand clinical phenotypes in different types of PLEC-related diseases. We suppose to design more well-organized research based on comprehensive knowledge about the genetic basis of plectinopathy diseases.
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Background: The phenotypic range of limb-girdle muscular dystrophies (LGMDs) varies significantly because of genetic heterogeneity ranging from very mild to severe forms. Molecular analysis of the DYSF gene is challenging due to the wide range of mutations and associated complications in interpretations of novel DYSF variants with uncertain significance. Thus, in the current study, we performed the NGS analysis and its results are confirmed with Sanger sequencing to find the plausible disease-causing variants in patients with muscular dystrophy and their relatives via segregation analysis. Materials and Methods: Nine patients with LGMD type 2B (LGMD2B) characteristics were screened for putative mutations by the whole-exome sequencing (WES) test. Either the patients themselves or their parents and first relatives were investigated in the segregation analysis through Sanger sequencing. The majority of variants were classified as pathogenic through American College of Medical Genetics and Genomics (ACMG) guidelines, segregation results, and in silico predictions. Results: Results revealed eight variants in DYSF gene, including three splicing (c.1149+4A>G, c.2864+1G>A, and c.5785-7G>A), two nonsense (p.Gln112Ter and p.Trp2084Ter), two missense (p.Thr1546Pro and p.Tyr1032Cys), and one frameshift (p.Asp1067Ilefs), among nine Iranian families. One of the eight identified variants was novel, including p.Asp1067Ilefs, which was predicted to be likely pathogenic based on the ACMG guidelines. Notably, prediction tools suggested the damaging effects of studied variants on dysferlin structure. Conclusion: Conclusively, the current report introduced eight variants including a novel frameshift in DYSF gene with noticeable pathogenic effects. This study significantly can broaden the diagnostic spectrum of LGMD2B in combination with previous reports about DYSF mutations and may pave the way for a rapidly high-ranked identification of the accurate type of dysferlinopathy.
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BACKGROUND: ECEL1 has been presented as a causal gene of an autosomal recessive form distal arthrogryposis (DA) which affects the distal joints. The present study focused on bioinformatic analysis of a novel mutation in ECEL1, c.535A>G (p. Lys179Glu), which was reported in a family with 2 affected boys and fetus through prenatal diagnosis. METHODS: Whole-exome sequencing data analyzed followed by molecular dynamic (MD) simulation of native ECEL1 protein and mutant structures using GROMACS software. One variant c.535A>G, p. Lys179Glu (homozygous) on gene ECEL1 has been detected in proband which was validated in all family members through Sanger sequencing. RESULTS: We demonstrated remarkable constructional differences by MD simulation between wild-type and novel mutant of ECEL1 gene. The reason for the lack of the Zn ion binding in mutation in the ECEL1 protein has been identified by average atomic distance and SMD analysis among the wild-type and mutant. CONCLUSION: Overall, in this study, we present knowledge of the effect of the studied variant on the ECEL1 protein leading to neurodegenerative disorder in humans. This work may hopefully be supplementary to classical molecular dynamics to dissolve the mutational effects of cofactor-dependent protein.
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Artrogripose , Simulação de Dinâmica Molecular , Masculino , Humanos , Fenótipo , Artrogripose/genética , Consanguinidade , Mutação , Metaloendopeptidases/genéticaRESUMO
Congenital myotonia is a non-dystrophic musculoskeletal disease that causes abnormal muscle relaxation. The prevalence of congenital disorders is notably high in Iran, emphasizing the importance of genetic assessment in suspicious cases. In this study, we aim to report cases with the chloride channel gene, CLCN1, mutations leading to significant morbidity. This case report study investigated four patients from four families with clinically defined congenital myotonia. Inclusion criteria were increased creatinine kinase (CK) and muscle stiffness. We collected data regarding family history, age of onset, and current therapeutic plan. All patients underwent skeletal muscle electromyography, cardiological evaluation, spirometry study, and hematochemistry assessment, including but not limited to muscle enzyme levels. Afterward, DNA was extracted from peripheral blood. Subsequently, whole exome sequencing (WES) and Sanger sequencing were done to detect and confirm variants, respectively. Age of onset ranged from 1 to 12 years in these patients, which are years apart from their first visit to the clinic. The warm-up phenomenon was present in all of them. A variant of uncertain clinical significance was found. We recommend that future research projects should study the efficiency of collaboration between clinicians, molecular geneticists, and other healthcare providers in order to find out about unclear variants as quickly as possible.
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Background: familial hypercholesterolemia (FH), a hereditary disorder, is caused by pathogenic variants in the LDLR, APOB, and PCSK9 genes. This study has assessed genetic variants in a family, clinically diagnosed with FH. Methods: A family was recruited from MASHAD study in Iran with possible FH based on the Simon Broom criteria. The DNA sample of an affected individual (proband) was analyzed using whole exome sequencing, followed by bioinformatics and segregation analyses. Results: A novel splice site variant (c.345-2A>G) was detected in the LDLRAP1 gene, which was segregated in all affected family members. Moreover, HMGCR rs3846662 g.23092A>G was found to be homozygous (G/G) in the proband, probably leading to reduced response to simvastatin and pravastatin. Conclusion: LDLRAP1 c.345-2A>G could alter the phosphotyrosine-binding domain, which acts as an important part of biological pathways related to lipid metabolism.
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Proteínas Adaptadoras de Transdução de Sinal/genética , Hiperlipoproteinemia Tipo II/genética , Sítios de Splice de RNA/genética , Adolescente , Adulto , Sequência de Bases , Segregação de Cromossomos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Farmacogenética , Adulto JovemRESUMO
INTRODUCTION: Dyslipidemia is a known risk factor for cardiovascular disease and is partially determined by genetic variations in the genes involved in lipoprotein metabolism. Therefore, we aimed to assess the association between a polymorphism of the Fatty Acid Binding Protein1 (rs2241883) gene locus and dyslipidemia in an Iranian cohort. MATERIALS AND METHODS: This is a case-control study 2737 individuals were recruited (2203 subjects with dyslipidemia and 534 controls). Dyslipidemia was defined as total cholesterol≥200 mg/dl, or TG≥150 mg/dl, or LDL-C≥130 mg/dl, or HDL-C<40 mg/dl in males and <50 mg/dl in females. Serum lipid profile was determined using a Alcyon Abbott biochemical auto analyzer, USA. Genotyping was made through double amplification refractory mutation system polymerase chain reaction (ARMs PCR). RESULT: The frequency of TT, CT, CC genotypes of rs2241883 polymorphism of FABP1 gene were 65.5, 33.4, 5.1 in subjects with dyslipidemia and 56.9%, 40.4%, 2.6% in subjects without dyslipidemia, respectively. Using a dominant genetic model, subjects carrying C allele (CC&CT genotypes) had a 22% lower risk of dyslipidemia (OR: 0.78, CI 95%: 0.62-0.98 P, 0.03). Individuals with CT vs. TT genotypes had a significantly lower risk of a high serum TC and LDL level. Further analysis showed that there was a positive association between FABP1 genotype (CT) and isolated HTG as well as combined dyslipidemia. The change of a polar amino acid (threonine) in position T94A to a hydrophobic amino acid (alanine) can cause transformation protein. CONCLUSIONS: A CC genotype of the rs2241883 polymorphism of the FABP1 gene appears to confer a higher risk of dyslipidemia in our representative cohort of Iranian individuals.
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Dislipidemias/genética , Proteínas de Ligação a Ácido Graxo/genética , Hipertrigliceridemia/genética , Adulto , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Irã (Geográfico) , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: There is a relationship between macro-nutrient-intakes and the genes implicated in lipid metabolism. In this study, we assessed the association between macro-and micro-nutrients dietary intakes with rs2241883 genetic variants of the FABP1 gene. METHODS: For this cross-sectional study 2737 subjects (including 2203 subjects with dyslipidemia and 534 healthy volunteers) were enrolled as part of the Mashhad Stroke and Heart Atherosclerotic Disorder (MASHAD) study cohort. Dyslipidemia was defined based on the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III). A NanoDrop®-1000 instrument was used to do the quantitation of DNA. The rs2241883 polymorphisms were genotyped using double ARMs PCR reactions. Genotyping reagents were obtained from Applied Biosystems. Dietary intake was evaluated using a food frequency questionnaire (FFQ) and validated by 2 consecutive 24-h food recalls. RESULTS: The results showed no significant association between subjects with and without dyslipidemia (P > 0.05), except for the zinc to copper ratio, the value for which was higher in the subjects with dyslipidemia (4.78 (1.62)) when compared to subjects without dyslipidemia (4.68 (1.82)) (p = 0.05). Using different genetic models we found that zinc and copper were significantly different in the additive (p = 0.01) and dominant (p = 0.01) genetic models. Although, this association was no longer significant after adjusting for confounding factors. CONCLUSIONS: There were no associations between macro-and micro-nutrient dietary intakes with rs2241883 genetic variants after adjusting for confounding factors in the MASHAD study population.
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Ingestão de Alimentos , Acidente Vascular Cerebral , Adulto , Estudos Transversais , Dieta , Humanos , NutrientesRESUMO
Statins are the first-line choice in Lipid-lowering therapy to reduce cardiovascular risk. In a continuous attempt to optimise treatment success, there is a need for additional research on genes and related molecular pathways that can determine the efficacy and toxicity of lipid-lowering drugs. Several variations within genes associated with lipid metabolism, including those involved in uptake, distribution and metabolism of statins have been reported. The purpose of this study was to evaluate the effect of genetic variations in the key genes responsible for statins' metabolism and their role in personalised medicine and pharmacogenetic testing (PGx) in patients treated with such drugs. Genetic assessment for specific known SNPs within the most known genes such as ABCG2, SLCO1B1, CYP3A4, and HMGCR, appears likely to predict the efficacy of statin therapy and prevent their side effects but does not necessarily reduce the risk of cardiovascular events. Key Messages Hypercholesterolaemia patients show different response to statin therapy. Several variations within genes associated with statin metabolism have been investigated. Genetic assessment for specific known SNPs within the most known genes may improve the efficacy of statins treatment and prevent their side effects.
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Doenças Cardiovasculares/epidemiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipercolesterolemia/tratamento farmacológico , Testes Farmacogenômicos/métodos , Medicina de Precisão/métodos , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/prevenção & controle , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Estudos de Viabilidade , Humanos , Hidroximetilglutaril-CoA Redutases/genética , Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/complicações , Hipercolesterolemia/genética , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Prognóstico , Medição de Risco/métodos , Resultado do TratamentoRESUMO
OBJECTIVES: Hepatocellular carcinoma (HCC) is one of the most significant health condition around the world. As the only curative therapies, liver transplantation and surgical resection are the clinical treatments of HCC. Due to the systemic toxicity and severe side effects of these treatments, it is vital to establish new therapeutic approaches. The present study aimed to compare cyclin D1 (CCN D1) gene expression in hepatocellular carcinoma cell line (HUH7) when it is treated with nanomicelle curcumin and sorafenib. The purpose was to identify toxicity risk and antioxidant activity of these drugs. MATERIALS AND METHODS: The toxic dose (IC50) of nanomicelle curcumin and sorafenib were detected after treatment of HUH7 cell lines with different dose of mentioned agents followed by MTT assay. CCN D1 gene expression was evaluated using real-time PCR. Following the Tukey's multiple comparison tests, statistical analysis is done through Student's t-test or ANOVA. RESULTS: The expression of the CCN D1 gene was statistically significant (P<0.001) at 289.31, 128 and 152.36 for sorafenib, nanomicelle curcumin and SNC (sorafenib-nanomicelle curcumin) respectively. The finding of this study revealed that, in comparison to sorafenib alone, the treatment of HUH7 with a nanomicelle curcumin IC50 dose, in combination with sorafenib, might down-regulate CCN D1 gene expression. CONCLUSION: The present research indicates that the treatment of the cell line with only nanomicelle curcumin results in the down-regulation of cyclin D1. To further decrease cyclin D1 expression, the co-delivery of curcumin and sorafenib appears to induce the apoptotic process. As a result, the effect of sorafenib cytotoxicity and CCN D1 gene expression decreases twofold.
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Curcumin is the principal polyphenolic compound present in turmeric with broad applications in tissue engineering and regenerative medicine. It has some important inherent properties with the potential to facilitate tissue healing, including anti-inflammatory, anti-oxidant, and antibacterial activities. Therefore, curcumin has been used for the treatment of various damaged tissues, especially wound injuries. There are different forms of curcumin, among which nano-formulations are of a great importance in regenerative medicine. It is also important to design sophisticated delivery systems for controlled/localized delivery of curcumin to the target tissues and organs. Although there are many reports on the advantages of this compound, further research is required to fully explore its clinical usage. The review describes the physicochemical and biological properties of curcumin and the current state of the evidence on its applications in tissue engineering. © 2018 BioFactors, 45(2):135-151, 2019.