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1.
Stem Cells ; 39(4): 458-466, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33442906

RESUMO

Development of the retina is regulated by growth factors, such as insulin-like growth factors 1 and 2 (IGF-1/2), which coordinate proliferation, differentiation, and maturation of the neuroepithelial precursors cells. In the circulation, IGF-1/2 are transported by the insulin growth factor binding proteins (IGFBPs) family members. IGFBPs can impact positively and negatively on IGF-1, by making it available or sequestering IGF-1 to or from its receptor. In this study, we investigated the expression of IGFBPs and their role in the generation of human retinal organoids from human pluripotent stem cells, showing a dynamic expression pattern suggestive of different IGFBPs being used in a stage-specific manner to mediate IGF-1 functions. Our data show that IGF-1 addition to culture media facilitated the generation of retinal organoids displaying the typical laminated structure and photoreceptor maturation. The organoids cultured in the absence of IGF-1, lacked the typical laminated structure at the early stages of differentiation and contained significantly less photoreceptors and more retinal ganglion cells at the later stages of differentiation, confirming the positive effects of IGF-1 on retinal lamination and photoreceptor development. The organoids cultured with the IGFBP inhibitor (NBI-31772) and IGF-1 showed lack of retinal lamination at the early stages of differentiation, an increased propensity to generate horizontal cells at mid-stages of differentiation and reduced photoreceptor development at the later stages of differentiation. Together these data suggest that IGFBPs enable IGF-1's role in retinal lamination and photoreceptor development in a stage-specific manner.


Assuntos
Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , Fator de Crescimento Insulin-Like II/genética , Fator de Crescimento Insulin-Like I/genética , Organoides/metabolismo , Células Fotorreceptoras de Vertebrados/metabolismo , Células-Tronco Pluripotentes/metabolismo , Catecóis/farmacologia , Diferenciação Celular/efeitos dos fármacos , Proteína Semelhante a ELAV 3/genética , Proteína Semelhante a ELAV 3/metabolismo , Proteína Semelhante a ELAV 4/genética , Proteína Semelhante a ELAV 4/metabolismo , Regulação da Expressão Gênica , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/antagonistas & inibidores , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like I/farmacologia , Fator de Crescimento Insulin-Like II/metabolismo , Isoquinolinas/farmacologia , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Organoides/citologia , Organoides/efeitos dos fármacos , Células Fotorreceptoras de Vertebrados/citologia , Células Fotorreceptoras de Vertebrados/efeitos dos fármacos , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/efeitos dos fármacos , Recoverina/genética , Recoverina/metabolismo , Transdução de Sinais , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , gama-Sinucleína/genética , gama-Sinucleína/metabolismo
2.
J Genet Couns ; 31(4): 922-936, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35194886

RESUMO

Genetic services are rapidly growing in the Arab world leading to increasing number of patients being diagnosed with genetic disorders. Islam is the only/major religion of the local population in these countries. Muslim patients integrate religion in virtually every aspect of their lives, and it is vital to understand the role of Islam on their coping and decision-making in the context of genetic counseling. This will help provide patients with the most appropriate services aligned to their religious beliefs and will improve outcomes. Increasing numbers of patients are being diagnosed with Long QT syndrome in Saudi Arabia. Using semi-structured interviews, this study explored the role of Islam on the lived experience of 13 Saudi participants diagnosed with autosomal dominant Long QT syndrome (3/13) or who are carriers of Jervell and Lange-Nielsen syndrome (10/13). The interviews investigated how they made sense of living with the condition in light of their religion/spirituality. The data were analyzed using interpretative phenomenological analysis and produced four superordinate themes: 1) Common belief and idiosyncratic interpretation; 2) Using religion to justify positive reframing of current illnesses; 3) Interplay between belief in medicine and in religion; and 4) Complex impact of diagnosis on religiosity. The results show that the participants' idiosyncratic interpretations of the religious principles, not the principles themselves, had an important influence on their coping, medical decision-making, perceptions regarding the cause of their disease, and compliance with medical advice. A novel insight of the current study is that the personal understanding and interpretation of medical information played the greatest role in the decision-making process, and not the religious beliefs. Thus, it is important for health professionals to give patients' information in a manner that is clear and detailed in order for them to facilitate an informed decision, and to ensure that they fully understand the implications.


Assuntos
Islamismo , Síndrome do QT Longo , Adaptação Psicológica , Humanos , Arábia Saudita
3.
Genomics ; 112(6): 5072-5085, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32920122

RESUMO

Myocardial infarction (MI) is the most prevalent coronary heart disease caused by the complex molecular interactions between multiple genes and environment. Here, we aim to identify potential biomarkers for the disease development and for prognosis of MI. We have used gene expression dataset (GSE66360) generated from 51 healthy controls and 49 patients experiencing acute MI and analyzed the differentially expressed genes (DEGs), protein-protein interactions (PPI), gene network-clusters to annotate the candidate pathways relevant to MI pathogenesis. Bioinformatic analysis revealed 810 DEGs. Their functional annotations have captured several MI targeting biological processes and pathways like immune response, inflammation and platelets degranulation. PPI network identify seventeen hub and bottleneck genes, whose involvement in MI was further confirmed by DisGeNET database. OpenTarget Platform reveal unique bottleneck genes as potential target for MI. Our findings identify several potential biomarkers associated with early stage MI providing a new insight into molecular mechanism underlying the disease.


Assuntos
Infarto do Miocárdio/genética , Biomarcadores , Expressão Gênica , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , MicroRNAs/metabolismo , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/metabolismo , Mapeamento de Interação de Proteínas , Biologia de Sistemas
4.
Brain ; 142(5): 1242-1254, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30968111

RESUMO

We describe a large consanguineous pedigree from a remote area of Northern Pakistan, with a complex developmental disorder associated with wide-ranging symptoms, including mental retardation, speech and language impairment and other neurological, psychiatric, skeletal and cardiac abnormalities. We initially carried out a genetic study using the HumanCytoSNP-12 v2.1 Illumina gene chip on nine family members and identified a single region of homozygosity shared amongst four affected individuals on chromosome 7p22 (positions 3059377-5478971). We performed whole-exome sequencing on two affected individuals from two separate branches of the extended pedigree and identified a novel nonsynonymous homozygous mutation in exon 9 of the WIPI2 (WD-repeat protein interacting with phosphoinositide 2) gene at position 5265458 (c.G745A;pV249M). WIPI2 plays a critical role in autophagy, an evolutionary conserved cellular pathway implicated in a growing number of medical conditions. The mutation is situated in a highly conserved and critically important region of WIPI2, responsible for binding PI(3)P and PI(3,5)P2, an essential requirement for autophagy to proceed. The mutation is absent in all public databases, is predicted to be damaging and segregates with the disease phenotype. We performed functional studies in vitro to determine the potential effects of the mutation on downstream pathways leading to autophagosome assembly. Binding of the V231M mutant of WIPI2b to ATG16L1 (as well as ATG5-12) is significantly reduced in GFP pull-down experiments, and fibroblasts derived from the patients show reduced WIPI2 puncta, reduced LC3 lipidation and reduced autophagic flux.


Assuntos
Autofagia/genética , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Proteínas de Membrana/genética , Mutação/genética , Proteínas de Ligação a Fosfato/genética , Adulto , Sequência de Aminoácidos , Células Cultivadas , Feminino , Células HEK293 , Humanos , Masculino , Proteínas de Membrana/química , Pessoa de Meia-Idade , Linhagem , Proteínas de Ligação a Fosfato/química , Estrutura Secundária de Proteína
5.
Nature ; 512(7513): 190-3, 2014 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-25043022

RESUMO

The Greenlandic population, a small and historically isolated founder population comprising about 57,000 inhabitants, has experienced a dramatic increase in type 2 diabetes (T2D) prevalence during the past 25 years. Motivated by this, we performed association mapping of T2D-related quantitative traits in up to 2,575 Greenlandic individuals without known diabetes. Using array-based genotyping and exome sequencing, we discovered a nonsense p.Arg684Ter variant (in which arginine is replaced by a termination codon) in the gene TBC1D4 with an allele frequency of 17%. Here we show that homozygous carriers of this variant have markedly higher concentrations of plasma glucose (ß = 3.8 mmol l(-1), P = 2.5 × 10(-35)) and serum insulin (ß = 165 pmol l(-1), P = 1.5 × 10(-20)) 2 hours after an oral glucose load compared with individuals with other genotypes (both non-carriers and heterozygous carriers). Furthermore, homozygous carriers have marginally lower concentrations of fasting plasma glucose (ß = -0.18 mmol l(-1), P = 1.1 × 10(-6)) and fasting serum insulin (ß = -8.3 pmol l(-1), P = 0.0014), and their T2D risk is markedly increased (odds ratio (OR) = 10.3, P = 1.6 × 10(-24)). Heterozygous carriers have a moderately higher plasma glucose concentration 2 hours after an oral glucose load than non-carriers (ß = 0.43 mmol l(-1), P = 5.3 × 10(-5)). Analyses of skeletal muscle biopsies showed lower messenger RNA and protein levels of the long isoform of TBC1D4, and lower muscle protein levels of the glucose transporter GLUT4, with increasing number of p.Arg684Ter alleles. These findings are concomitant with a severely decreased insulin-stimulated glucose uptake in muscle, leading to postprandial hyperglycaemia, impaired glucose tolerance and T2D. The observed effect sizes are several times larger than any previous findings in large-scale genome-wide association studies of these traits and constitute further proof of the value of conducting genetic association studies outside the traditional setting of large homogeneous populations.


Assuntos
Diabetes Mellitus Tipo 2/genética , Proteínas Ativadoras de GTPase/genética , Variação Genética , Resistência à Insulina/genética , Adulto , Glicemia/análise , Códon sem Sentido/genética , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Groenlândia , Humanos , Insulina/sangue , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo
6.
Am J Hum Genet ; 99(5): 1181-1189, 2016 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-27773428

RESUMO

Cobblestone lissencephaly (COB) is a severe brain malformation in which overmigration of neurons and glial cells into the arachnoid space results in the formation of cortical dysplasia. COB occurs in a wide range of genetic disorders known as dystroglycanopathies, which are congenital muscular dystrophies associated with brain and eye anomalies and range from Walker-Warburg syndrome to Fukuyama congenital muscular dystrophy. Each of these conditions has been associated with alpha-dystroglycan defects or with mutations in genes encoding basement membrane components, which are known to interact with alpha-dystroglycan. Our screening of a cohort of 25 families with recessive forms of COB identified six families affected by biallelic mutations in TMTC3 (encoding transmembrane and tetratricopeptide repeat containing 3), a gene without obvious functional connections to alpha-dystroglycan. Most affected individuals showed brainstem and cerebellum hypoplasia, as well as ventriculomegaly. However, the minority of the affected individuals had eye defects or elevated muscle creatine phosphokinase, separating the TMTC3 COB phenotype from typical congenital muscular dystrophies. Our data suggest that loss of TMTC3 causes COB with minimal eye or muscle involvement.


Assuntos
Alelos , Proteínas de Transporte/genética , Lissencefalia Cobblestone/genética , Proteínas de Membrana/genética , Sequência de Aminoácidos , Membrana Basal/metabolismo , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Proteínas de Transporte/metabolismo , Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Lissencefalia Cobblestone/diagnóstico por imagem , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/genética , Distroglicanas/metabolismo , Anormalidades do Olho/diagnóstico por imagem , Anormalidades do Olho/genética , Feminino , Humanos , Lactente , Masculino , Proteínas de Membrana/metabolismo , Mutação , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/genética , Neuroglia/metabolismo , Neurônios/patologia , Linhagem , Fenótipo
7.
Cancer Cell Int ; 19: 191, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31367189

RESUMO

BACKGROUND: Doxorubicin (DOX) is one of the most important anticancer agents used in treating breast cancer. However, chronic cardiotoxicity and multidrug resistance limit the chemotherapeutic use of DOX. METHODS: This study aimed to evaluate the capability of calcium channel blocker diltiazem (DIL) to reverse DOX resistance in breast cancer MCF-7 cells and to confer protection against DOX-induced cardiotoxicity in Wistar rats. For this purpose, we explored the effects of DOX on cell cycle phase distribution and expression of ABCB1, FOXO3a, and p53 genes in the presence and absence of DIL (20 µg/ml) and studied the ability of DIL to prevent DOX-induced cardiotoxicity after a single injection of DOX (15 mg/kg) in male Wister rats. RESULTS: We found that compared with DOX alone treatment, DIL + DOX treatment down regulated the ABCB1 gene expression by > fourfold but up regulated the FOXO3a and p53 genes expression by 1.5 fold. DIL treatment conferred protection against DOX-induced cardiotoxicity, as indicated by a decrease in the levels of the cardiac enzyme creatine kinase MB and malondialdehyde and an increase in the total antioxidant capacity and glutathione peroxidase levels. These biochemical results were further confirmed by the histopathological investigation of cardiac cells, which showed normal cardiac cells with central vesicular nuclei and prevention of DOX-induced disruption of normal cardiac architecture in the DIL to DOX group. CONCLUSIONS: Taken together, our results indicate that DIL treatment can reverse the resistance of breast cancer cells to the therapeutic effects of DOX and can protect against DOX-induced cardiotoxicity in rats.

8.
Gut ; 66(1): 70-78, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-26408641

RESUMO

OBJECTIVE: To evaluate the potential for diagnosing colorectal cancer (CRC) from faecal metagenomes. DESIGN: We performed metagenome-wide association studies on faecal samples from 74 patients with CRC and 54 controls from China, and validated the results in 16 patients and 24 controls from Denmark. We further validated the biomarkers in two published cohorts from France and Austria. Finally, we employed targeted quantitative PCR (qPCR) assays to evaluate diagnostic potential of selected biomarkers in an independent Chinese cohort of 47 patients and 109 controls. RESULTS: Besides confirming known associations of Fusobacterium nucleatum and Peptostreptococcus stomatis with CRC, we found significant associations with several species, including Parvimonas micra and Solobacterium moorei. We identified 20 microbial gene markers that differentiated CRC and control microbiomes, and validated 4 markers in the Danish cohort. In the French and Austrian cohorts, these four genes distinguished CRC metagenomes from controls with areas under the receiver-operating curve (AUC) of 0.72 and 0.77, respectively. qPCR measurements of two of these genes accurately classified patients with CRC in the independent Chinese cohort with AUC=0.84 and OR of 23. These genes were enriched in early-stage (I-II) patient microbiomes, highlighting the potential for using faecal metagenomic biomarkers for early diagnosis of CRC. CONCLUSIONS: We present the first metagenomic profiling study of CRC faecal microbiomes to discover and validate microbial biomarkers in ethnically different cohorts, and to independently validate selected biomarkers using an affordable clinically relevant technology. Our study thus takes a step further towards affordable non-invasive early diagnostic biomarkers for CRC from faecal samples.


Assuntos
Biomarcadores Tumorais , Neoplasias Colorretais/diagnóstico , Disbiose/microbiologia , Fezes/microbiologia , Microbioma Gastrointestinal/genética , Idoso , Área Sob a Curva , Áustria , Estudos de Casos e Controles , China , Estudos de Coortes , Neoplasias Colorretais/complicações , Dinamarca , Disbiose/complicações , Feminino , Firmicutes/isolamento & purificação , França , Fusobacterium nucleatum/isolamento & purificação , Estudo de Associação Genômica Ampla , Humanos , Masculino , Metagenômica , Pessoa de Meia-Idade , Peptostreptococcus/isolamento & purificação , Curva ROC
9.
J Cell Biochem ; 118(8): 2193-2207, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28059456

RESUMO

Celiac disease (CD) is a gluten intolerance disorder with known genetic contribution. The recent fine mapping and genome-wide association studies (GWAS) have identified up to 57 non-HLA CD susceptibility SNPs, majority of which are non-coding variants lacking any functional annotation. Therefore, we adopted multidimensional computational approach for uncovering the plausible mechanisms through which these GWAS SNPs are connected to CD pathogenesis. At initial phase, we identified that 25 (43.85%) out of 57 CD-SNPs lies in evolutionarily constrained genetic element regions. In follow-up phases, through computational (CADD, GWAVA, and FATHMM algorithms) deleterious intensity measurements, we have discovered that 42 (3.94%) out of 1065 variants (57 CD-lead and 1008-linked SNPs; r2 ≥ 0.8) are differentially deleterious in nature to CD. Further functional scrutinization of these CD variants by public domain eQTL mapping, gene expression, knockout mouse model, and pathway analyses revealed that deleterious SNPs of CCR2 gene influences its expression levels and may also elicit a cascade of T-cell-mediated immunological events leading to intestinal gluten intolerance in genetically susceptible individuals. This study demonstrates the utility of integrated in silico analysis of annotations, gene expression, and pathways in prioritizing the potential complex disease variants from large-scale open source genomic data. J. Cell. Biochem. 118: 2193-2207, 2017. © 2017 Wiley Periodicals, Inc.


Assuntos
Doença Celíaca/metabolismo , Doença Celíaca/patologia , Biologia Computacional/métodos , Estudo de Associação Genômica Ampla/métodos , Receptores CCR2/genética , Algoritmos , Animais , Doença Celíaca/genética , Predisposição Genética para Doença/genética , Humanos , Camundongos , Camundongos Knockout , Polimorfismo de Nucleotídeo Único/genética
10.
J Cell Biochem ; 117(9): 2023-35, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26813965

RESUMO

Genetic mutations in MED12, a subunit of Mediator complex are seen in a broad spectrum of human diseases. However, the underlying basis of how these pathogenic mutations elicit protein phenotype changes in terms of 3D structure, stability and protein binding sites remains unknown. Therefore, we aimed to investigate the structural and functional impacts of MED12 mutations, using computational methods as an alternate to traditional in vivo and in vitro approaches. The MED12 gene mutations details and their corresponding clinical associations were collected from different databases and by text-mining. Initially, diverse computational approaches were applied to categorize the different classes of mutations based on their deleterious impact to MED12. Then, protein structures for wild and mutant types built by integrative modeling were analyzed for structural divergence, solvent accessibility, stability, and functional interaction deformities. Finally, this study was able to identify that genetic mutations mapped to exon-2 region, highly conserved LCEWAV and Catenin domains induce biochemically severe amino acid changes which alters the protein phenotype as well as the stability of MED12-CYCC interactions. To better understand the deleterious nature of FS-IDs and Indels, this study asserts the utility of computational screening based on their propensity towards non-sense mediated decay. Current study findings may help to narrow down the number of MED12 mutations to be screened for mediator complex dysfunction associated genetic diseases. This study supports computational methods as a primary filter to verify the plausible impact of pathogenic mutations based on the perspective of evolution, expression and phenotype of proteins. J. Cell. Biochem. 117: 2023-2035, 2016. © 2016 Wiley Periodicals, Inc.


Assuntos
Complexo Mediador , Mutação , Proteólise , Substituição de Aminoácidos , Simulação por Computador , Humanos , Complexo Mediador/química , Complexo Mediador/genética , Complexo Mediador/metabolismo , Domínios Proteicos , Relação Estrutura-Atividade
11.
Stem Cells ; 33(9): 2643-51, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26033645

RESUMO

Genetic cardiac diseases are major causes of morbidity and mortality. Although animal models have been created to provide some useful insights into the pathogenesis of genetic cardiac diseases, the significant species differences and the lack of genetic information for complex genetic diseases markedly attenuate the application values of such data. Generation of induced pluripotent stem cells (iPSCs) from patient-specific specimens and subsequent derivation of cardiomyocytes offer novel avenues to study the mechanisms underlying cardiac diseases, to identify new causative genes, and to provide insights into the disease aetiology. In recent years, the list of human iPSC-based models for genetic cardiac diseases has been expanding rapidly, although there are still remaining concerns on the level of functionality of iPSC-derived cardiomyocytes and their ability to be used for modeling complex cardiac diseases in adults. This review focuses on the development of cardiomyocyte induction from pluripotent stem cells, the recent progress in heart disease modeling using iPSC-derived cardiomyocytes, and the challenges associated with understanding complex genetic diseases. To address these issues, we examine the similarity between iPSC-derived cardiomyocytes and their ex vivo counterparts and how this relates to the method used to differentiate the pluripotent stem cells into a cardiomyocyte phenotype. We progress to examine categories of congenital cardiac abnormalities that are suitable for iPSC-based disease modeling.


Assuntos
Cardiopatias/patologia , Células-Tronco Pluripotentes Induzidas/patologia , Miócitos Cardíacos/patologia , Animais , Diferenciação Celular/fisiologia , Células Cultivadas , Cardiopatias/fisiopatologia , Humanos , Células-Tronco Pluripotentes Induzidas/fisiologia , Miócitos Cardíacos/fisiologia
12.
Cleft Palate Craniofac J ; 53(4): 435-43, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26402721

RESUMO

OBJECTIVES: Nonsyndromic orofacial cleft (NSOFC) etiology is multifactorial and heterogeneous. This study aimed to identify environmental risk factors related to NSOFC in the Western Region of Saudi Arabia. METHODS: A case-control study carried out in seven hospitals in two main cities (Jeddah and Maddina) over 2 years on parents of 112 infants with NSOFC (infants were also examined) and 138 infant controls, matched for age (<18 months), gender, and location, completed a questionnaire on 3-month pregestation and first trimester events. RESULTS: There was significantly increased NSOFC risk with twin pregnancies (P = .01, odds ratio [OR] = 9.5, 95% confidence interval [CI]: 1.15 to 78.4), maternal antibiotic use (P = .021, OR = 2.71, 95% CI: 1.11 to 6.62), antiemetic medication (P = .005, OR = 2.85, 95% CI: 1.3 to 6), severe morning sickness (P = .006, OR = 3.6, 95% CI: 1.34 to 9.65), illness (P = .009, OR = 2.19, 95% CI: 1.17 to 4.08), common cold/flu (P = .003, OR = 3.32, 95% CI: 1.48 to 7.58), Jorak smoking (P = .004, OR = 14.07, 95% CI: 1.55 to 128.1), and passive smoking (P = .05, OR = 2.05, 95% CI: 1.05 to 4.01). Reduced NSOFC risk was found with calcium supplementation (P = .02, OR = 0.32, 95% CI: 0.11 to 0.88), incense use (P = .03, OR = 0.58, 95% CI: 0.34 to 0.98), and maternal drinking water, with Zamzam water (which contains a high concentration of minerals) showing a significant protective effect compared with tap water (P = .01, 95% CI: 0.06 to 0.6) and bottled water (P = .02, 95% CI: 0.03 to 0.57). CONCLUSION: Twin births, maternal antibiotic use, antiemetic medication, severe morning sickness, common cold/flu, Jorak smoking, and passive smoking were associated with infants born with NSOFC. Calcium supplementation, incense use, and Zamzam water reduced the risk of NSOFC, raising the possibility of community preventive programs.


Assuntos
Fenda Labial/etiologia , Fissura Palatina/etiologia , Estudos de Casos e Controles , Feminino , Humanos , Gravidez , Fatores de Risco , Arábia Saudita/epidemiologia
13.
Ann Hum Genet ; 79(5): 350-356, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26102279

RESUMO

Dystrophic epidermolysis bullosa (DEB) is an inherited skin disorder with variable severity and heterogeneous genetic involvement. Diagnostic approaches for this condition include clinical evaluations and electron microscopy of patients' skin biopsies, followed by Sanger sequencing (SS) of a large gene (118 exons) that encodes the alpha chain of type VII collagen (COL7A1) located on Chromosome 3p21.1. However, the use of SS may hinder diagnostic efficiency and lead to delays because it is costly and time-consuming. We evaluated a 5-generation consanguineous family with 3 affected individuals presenting the severe generalised DEB phenotype. Human whole-exome sequencing (WES) revealed 2 homozygous sequence variants: the previously reported variant p.Arg578* in exon 13 and a novel variant p.Arg2063Gln in exon 74 of the COL7A1 gene. Validation by SS, performed on all family members, confirmed the cosegregation of the 2 variants with the disease phenotype. To the best of our knowledge, 2 homozygous COL7A1 variants have never been simultaneously reported in DEB patients; however, the upstream protein truncation variant is more likely to be disease-causing than the novel missense variant. WES can be used as an efficient molecular diagnostic tool for evaluating autosomal recessive forms of DEB.

14.
Stem Cells ; 32(9): 2291-8, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24740867

RESUMO

Although certainly one of the most recognizable characteristics of human biology, aging remains one of the least understood. This is largely attributable to the fact that aging is both gradual and inherently complex, with almost all aspects of physiology and phenotype undergoing steady modification with advancing age. The complexity of the aging process does not allow for a single all-encompassing definition, yet decades of study using diverse systems, methodologies, and model organisms have begun to build a consensus regarding the central physiological characteristics of aging. Indeed, such studies have shown that the process of aging is invariably accompanied by a diminished capacity to adequately maintain tissue homeostasis or to repair tissues after injury. When homeostatic control diminishes to the point at which tissue/organ integrity and function are no longer sufficiently maintained, physiologic decline ensues, and aging is manifested. Inadequate organ homeostasis indicates possible dysfunction of tissue-specific stem cells. Several mechanisms have been postulated to account for age-related cellular changes; however, increasing literature evidence suggests that age-related changes to the epigenome make a major contribution to the aged phenotype. In this review, we discuss the evidence for epigenetic contributions to tissue-specific stem cell ageing.


Assuntos
Senescência Celular/genética , Células-Tronco/fisiologia , Animais , Epigênese Genética , Humanos , Células-Tronco/citologia
15.
J Cell Biochem ; 115(2): 313-27, 2014 02.
Artigo em Inglês | MEDLINE | ID: mdl-24038392

RESUMO

Aberrant glycosylation by N-acetylgalactosaminyl transferases (GALNTs) is a well-described pathological alteration that is widespread in hereditary diseases, prominently including human cancers, familial tumoral calcinosis and hyperostosis-hyperphosphatemia. In this study, we integrated different computational tools to perform the in silico analysis of clinically significant mutations (nsSNPs/single amino acid change) at both functional and structural levels, found in human GALNT3, GALNT8, GALNT12, and GALNT13 genes. From function and structure based insights, mutations encoding R162Q, T359K, C574G, G359D, R297W, D303N, Y396C, and D313N substitutions were concordantly predicted highly deleterious for relevant GALNTs proteins. From intriguing findings, T359K-GALNT3 was simulated with high contribution for disease susceptibility (tumor calcinosis) as compared to its partner variant T272K (Ichikawa et al. [2006] J. Clin. Endocrinol. Metab. 91:4472-4475). Similarly, the prediction of high damaging behavior, evolutionary conservation and structural destabilization for C574G were proposed as major contributing factors to regulate metabolic disorder underlying tumor calcinosis and hyperostosis-hyperphosphatemia syndrome. In case of R297W-GALNT12, prediction of highly deleterious effect and disruption in ionic interactions were anticipated with reduction in enzymatic activity, associated with bilateral breast cancer and primary colorectal cancers. The second GALNT12 mutation (D303N)-known splice variant-was predicted with disease severity as a result of decrease in charge density and buried behavior neighboring the catalytic B domain. In the lack of adequate in silico data about systematic characterization of clinically significant mutations in GALNTs genes, current study can be used as a significant tool to interpret the role of GALNTs reaction chemistry in disease-association risks in body.


Assuntos
Calcinose/genética , N-Acetilgalactosaminiltransferases/genética , Calcinose/patologia , Simulação por Computador , Suscetibilidade a Doenças , Humanos , Mutação de Sentido Incorreto/genética , Polimorfismo de Nucleotídeo Único , Relação Estrutura-Atividade , Polipeptídeo N-Acetilgalactosaminiltransferase
16.
Mol Genet Genomics ; 289(4): 533-40, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24604425

RESUMO

Coronary artery disease (CAD) is a multifactorial disease with the underlying involvement of environment, life style and nuclear genetics. However, the role of extranuclear genetic material in terms of somatically acquired mutations in mitochondrial tRNA and protein coding genes in the initiation or progression of CAD is not well defined. Hence, in the present study, right atrial appendage tissues and matched blood samples of 150 CAD patients were screened for mutations in nucleotide regions encompassing the Cytochrome c oxidase subunit II (MT-CO2), tRNA lysine (MT-TK), ATP synthase F0 subunit 8 (MT-ATP8) and Cytochrome b (MT-CYB) genes of mitochondrial DNA. We have found 9 different somatic mutations in 6 % of the CAD patients. Out of these mutations, 4 each were localized in MT-TK gene (T8324A, A8326G, A8331G and A8344G) and MT-CYB genes (T15062C, C15238A, T15378G and C15491G) in addition to one mutation in non-coding region 7 (A8270T) of mitochondrial genome. In addition, we noticed that majority (85.3 %) of CAD patients showed double repeats of germ-line "CCCCCTCTA" intergenic sequence between MT-CO2 and MT-TK genes. Our in-silico investigations of missense mutations revealed that they may alter the free energy and stability of polypeptide chains of MT-CYB protein of complex III of mitochondrial respiratory chain. Based on our study findings, we hypothesize that the somatically acquired variations in MT-TK and MT-CYB genes may negatively impact the energy metabolism of cardiomyocytes in right atrial appendage tissues and contribute in the cardiac dysfunction among CAD patients. In conclusion, our findings may be likely to have potential implications in understanding the disease pathophysiology, diagnosis as well as for the better therapeutic management of CAD patients.


Assuntos
Doença da Artéria Coronariana/genética , DNA Mitocondrial/genética , Genoma Mitocondrial/genética , Mutação , Placa Aterosclerótica/genética , Apêndice Atrial , Biópsia , Complexo IV da Cadeia de Transporte de Elétrons/genética , Feminino , Genes Mitocondriais/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/genética , Modelos Moleculares , Fosforilação Oxidativa , Análise de Sequência de DNA
17.
Stem Cells ; 31(9): 2015-23, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23818183

RESUMO

Cernunnos (also known as XLF) deficiency syndrome is a rare recessive autosomal disorder caused by mutations in the XLF gene, a key factor involved in the end joining step of DNA during nonhomologous end joining (NHEJ) process. Human patients with XLF mutations display microcephaly, developmental and growth delays, and severe immunodeficiency. While the clinical phenotype of DNA damage disorders, including XLF Syndrome, has been described extensively, the underlying mechanisms of disease onset, are as yet, undefined. We have been able to generate an induced pluripotent stem cell (iPSC) model of XLF deficiency, which accurately replicates the double-strand break repair deficiency observed in XLF patients. XLF patient-specific iPSCs (XLF-iPSC) show typical expression of pluripotency markers, but have altered in vitro differentiation capacity and an inability to generate teratomas comprised of all three germ layers in vivo. Our results demonstrate that XLF-iPSCs possess a weak NHEJ-mediated DNA repair capacity that is incapable of coping with the DNA lesions introduced by physiological stress, normal metabolism, and ionizing radiation. XLF-iPSC lines are capable of hematopoietic differentiation; however, the more primitive subsets of hematopoietic progenitors display increased apoptosis in culture and an inability to repair DNA damage. Together, our findings highlight the importance of NHEJ-mediated-DNA repair in the maintenance of a pristine pool of hematopoietic progenitors during human embryonic development.


Assuntos
Enzimas Reparadoras do DNA/deficiência , Proteínas de Ligação a DNA/deficiência , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Modelos Biológicos , Sequência de Bases , Diferenciação Celular , Linhagem Celular , Sobrevivência Celular , Quebras de DNA de Cadeia Dupla , Reparo do DNA por Junção de Extremidades , Enzimas Reparadoras do DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Dados de Sequência Molecular
18.
Mol Biol Rep ; 41(2): 841-8, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24381101

RESUMO

In the present cross sectional study, we aimed to ascertain the relative associations of GST genotypes with GST activity variations and also with the risk to DMT2 predisposition among men and women separately. Clinical samples obtained from 244 DMT2 cases (120 Males and 124 Females) and 228 controls (117 Males and 111 Females) belonging to Asian Indian ethnicity were used to test for glycemic index, lipid profile, GST activity and GST genotypes. The frequencies of single and combinations of GST genotypes were statistically examined for their association with DMT2 risk among both study groups. The GST activity is significantly lowered in DMT2 group compared to controls (p = < 0.001). This reduction is found to be subjective to single and combinations of GST genotypes among diabetic patients. The frequency distribution for single, double and triple combinations of genotypes of GSTT1, GSTM1 and GSTP1 showed the varying degrees of association with DMT2 risk from 0.5 to 5.6-fold among male and female patients (for all associations, p value was <0.05). Interestingly, GST activity was lowered in both male and female patients with single or combinational genotypes of GSTM1 (Null), GSTT1 (Null), and P1 (V/V) (for all associations, p value was = <0.0001). The reduced anti-oxidant capacity among diabetic patients with certain GST genotypes may have some important implications for disease diagnosis and therapy.


Assuntos
Diabetes Mellitus Tipo 2/genética , Glutationa S-Transferase pi/genética , Glutationa Transferase/genética , Adulto , Diabetes Mellitus Tipo 2/enzimologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/genética , Polimorfismo Genético , Fatores de Risco
19.
Genomics ; 99(6): 330-9, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22564471

RESUMO

In the present study, nsSNPs in EPHX1, GSTT1, GSTM1 and GSTP1 genes were screened for their functional impact on concerned proteins and their plausible role in breast cancer susceptibility. Initially, SNPs were retrieved from dbSNP, followed by identification of potentially deleterious nsSNPs using PolyPhen and SIFT. Functional analysis was done with SNPs3D, SNPs&GO and MutPred methods. Prediction and evaluation of the functional impact on the 3D structure of proteins were performed with Swiss PDB viewer and NOMAD-Ref servers. On analysis, 13 nsSNPs were found to be highly deleterious and damaging to the protein structure, of which 6 nsSNPs, rs45549733, rs45506591 and rs4986949 of GSTP1, rs72549341 and rs148240980 of EPHX1 and rs17856199 of GSTT1 were predicted to be potentially polymorphic. It is therefore hypothesized that the 6 identified nsSNPs may alter the detoxification process and elevate carcinogenic metabolite accumulation thus modifies the risk of breast cancer susceptibility in a group of women.


Assuntos
Neoplasias da Mama/genética , Epóxido Hidrolases/genética , Glutationa S-Transferase pi/genética , Glutationa Transferase/genética , Polimorfismo de Nucleotídeo Único , Feminino , Predisposição Genética para Doença , Testes Genéticos/métodos , Humanos , Conformação Proteica
20.
Gene ; 851: 146909, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36162527

RESUMO

BACKGROUND: Tetralogy of Fallot (TOF) is a rare, complex congenital heart defect caused by genetic and environmental interactions that results in abnormal heart development during the early stages of pregnancy. Genetic basis of TOF in Saudi populations is not yet studied. Therefore, the objective of this study is to screen for the molecular defects causing TOF in Saudi patients. METHODS: A family with non-syndromic TOF was recruited from the Western region of Saudi Arabia. Whole exome sequencing (WES) was performed on the proband and her parents. The identified candidate variant was verified by sanger sequencing. Also, different computational biology tools were used to figure out how candidate variants affect the structure and function of candidate protein involved in TOF. RESULTS: A novel heterozygous de novo mutation in LRP1 (p. G3311D) gene was identified in the index case. Also, this variant was absent in the in-house exome sequencing data of 80 healthy Saudi individuals. This variant was predicted to be likely pathogenic, as it negatively affects the biophysical chemical properties and stability of the protein. Furthermore, functional biology data from knock out mouse models confirms that molecular defects in LRP1 gene leads to cardiac defects and lethality. This variant was not previously reported in both Arab and global population genetic databases. CONCLUSION: The findings in this study postulate that the LRP1 variant has a role in TOF pathogenesis and facilitate accurate diagnosis as well as the understanding of underlying molecular mechanisms and pathophysiology of the disease.


Assuntos
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Tetralogia de Fallot , Animais , Feminino , Camundongos , Exoma/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Mutação , Linhagem , Arábia Saudita , Tetralogia de Fallot/genética , Tetralogia de Fallot/patologia , Humanos
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