RESUMO
AIMS: Osteoporosis (OP) remains a major public health problem worldwide. The most serious complications of this disease are fragility fractures, which increase morbidity and mortality. Management of OP represents an economic burden for health systems. Therefore, it is necessary to develop new screening strategies to identify the population at risk and implement preventive measures. We previously identified the SNPs rs3801387 in WNT16, rs7108738 in SOX6, rs10036727 in SLIT3 and rs7584262 in PKDCC as associated with bone mineral density in postmenopausal women through a genome-wide association study. The aim of this study was to validate those SNPs in two independent cohorts of non-related postmenopausal women. MATERIALS AND METHODS: We included 1160 women classifying them as normal, osteopenic or osteoporotic and a group with hip fragility fracture. Genotyping was performed using predesigned TaqMan assays. RESULTS: The variants rs10036727 and rs7108738 showed a significant association with BMD at the femoral neck. SLIT3 has been previously proposed as a potential biomarker and therapeutic resource. CONCLUSIONS: Our results provide new evidence regarding a possible involvement of SLIT3 in bone metabolisms and encourage the development of more studies in different populations to support these observations.
Assuntos
Densidade Óssea/genética , Proteínas de Membrana/genética , Osteoporose Pós-Menopausa/genética , Fatores de Transcrição SOXD/genética , Absorciometria de Fóton , Idoso , Doenças Ósseas Metabólicas/genética , Feminino , Colo do Fêmur/diagnóstico por imagem , Fraturas do Quadril/genética , Humanos , Vértebras Lombares/diagnóstico por imagem , México , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/diagnóstico por imagem , Fraturas por Osteoporose/genética , Polimorfismo de Nucleotídeo Único , Pós-Menopausa , Proteínas Tirosina Quinases/genética , Proteínas Wnt/genéticaRESUMO
Precise control of neurite guidance during development is essential to ensure proper formation of neuronal networks and correct function of the central nervous system (CNS). How neuronal projections find their targets to generate appropriate synapses is not entirely understood. Although transcription factors are key molecules during neurogenesis, we do not know their entire function during the formation of networks in the CNS. Here, we used the Drosophila melanogaster optic lobe as a model for understanding neurite guidance during development. We assessed the function of Sox102F/SoxD, the unique Drosophila orthologue of the vertebrate SoxD family of transcription factors. SoxD is expressed in immature and mature neurons in the larval and adult lobula plate ganglia (one of the optic lobe neuropils), but is absent from glial cells, neural stem cells and progenitors of the lobula plate. SoxD RNAi knockdown in all neurons results in a reduction of the lobula plate neuropil, without affecting neuronal fate. This morphological defect is associated with an impaired optomotor response of adult flies. Moreover, knocking down SoxD only in T4/T5 neuronal types, which control motion vision, affects proper neurite guidance into the medulla and lobula. Our findings suggest that SoxD regulates neurite guidance, without affecting neuronal fate.
Assuntos
Proteínas de Drosophila/metabolismo , Rede Nervosa/metabolismo , Neuritos/metabolismo , Neurópilo/metabolismo , Fatores de Transcrição SOXD/metabolismo , Vias Visuais/metabolismo , Animais , Proteínas de Drosophila/genética , Drosophila melanogaster , Rede Nervosa/citologia , Neurópilo/citologia , Fatores de Transcrição SOXD/genética , Vias Visuais/citologiaRESUMO
Hereditary persistence of fetal hemoglobin deletion type-2 (HPFH-2) and Sicilian-δß-thalassemia are conditions described as large deletions of the human ß-like globin cluster, with absent ß-globin chains and a compensatory variable increase in γ-globin. HPFH, in general, may be distinguished from DB-Thalassemia by higher fetal hemoglobin (HbF) levels, absence of anemia and hypochromic and microcytic erythrocytes. MicroRNAs (miRNAs) regulate a range of cellular processes including erythropoiesis and regulation of transcription factors such as the BCL11A and SOX6 genes, which are related to the regulation of γ-globin expression. In this report, a possible association among the overexpression of miRNAs and the expression of the γ-globin gene was analyzed in these two conditions. Forty-nine differentially expressed miRNAs were identified by microarrays in CD34+-derived erythroid cells of two subjects heterozygous for Sicilian-δß-thalassemia, 2 for HPFH-2 and 3 for controls after 13 days of culture. Some of these miRNAs may participate in γ-globin gene regulation and red blood cell function. The BCL11A gene was found to be potentially targeted by 12 miRNAs that were up-regulated in HPFH-2 or in DB-Thal. A down-regulation of BCL11A gene expression in HPFH-2 was verified by quantitative polymerase chain reaction. These data suggest an important action for miRNA that may partially explain the phenotypic differences between HPFH-2 and Sicilian δß-thalassemia and the increased expression of γ-globin in these conditions.
Assuntos
Proteínas de Transporte/genética , Hemoglobina Fetal/genética , MicroRNAs/genética , Proteínas Nucleares/genética , Fatores de Transcrição SOXD/genética , Globinas beta/genética , Talassemia beta/genética , Talassemia delta/genética , gama-Globinas/genética , Antígenos CD34/metabolismo , Sequência de Bases , Regulação para Baixo/genética , Feminino , Humanos , Masculino , MicroRNAs/biossíntese , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Repressoras , Análise de Sequência de DNA , Deleção de Sequência/genética , gama-Globinas/metabolismoRESUMO
The acrofacial dysostoses (AFD) are a genetically heterogeneous group of inherited disorders with craniofacial and limb abnormalities. Rodriguez syndrome is a severe, usually perinatal lethal AFD, characterized by severe retrognathia, oligodactyly and lower limb abnormalities. Rodriguez syndrome has been proposed to be a severe form of Nager syndrome, a non-lethal AFD that results from mutations in SF3B4, a component of the U2 small nuclear ribonucleoprotein particle (U2 snRNP). Furthermore, a case with a phenotype intermediate between Rodriguez and Nager syndromes has been shown to have an SF3B4 mutation. We identified heterozygosity for SF3B4 mutations in Rodriguez syndrome, confirming that the phenotype is a dominant disorder that is allelic with Nager syndrome. The mutations led to reduced SF3B4 synthesis and defects in mRNA splicing, primarily exon skipping. The mutations also led to reduced expression in growth plate chondrocytes of target genes, including the DLX5, DLX6, SOX9, and SOX6 transcription factor genes, which are known to be important for skeletal development. These data provide mechanistic insight toward understanding how SF3B4 mutations lead to the skeletal abnormalities observed in the acrofacial dysostoses.
Assuntos
Condrócitos/metabolismo , Deformidades Congênitas da Mão/genética , Disostose Mandibulofacial/genética , Mutação , Fatores de Processamento de RNA/genética , Splicing de RNA , Adulto , Células Cultivadas , Feminino , Deformidades Congênitas da Mão/diagnóstico por imagem , Deformidades Congênitas da Mão/patologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Recém-Nascido , Masculino , Disostose Mandibulofacial/diagnóstico por imagem , Disostose Mandibulofacial/patologia , Linhagem , Fenótipo , Fatores de Processamento de RNA/metabolismo , Fatores de Transcrição SOXD/genética , Fatores de Transcrição SOXD/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
BACKGROUND: Left ventricular mass (LVM) is an important risk factor for cardiovascular disease. Previously we found evidence for linkage to chromosome 12p11 in Dominican families, with a significant increase in a subset of families with high average waist circumference (WC). In the present study, we use association analysis to further study the genetic effect on LVM. METHODS: Association analysis with LVM was done in the one LOD critical region of the linkage peak in an independent sample of 897 Caribbean Hispanics. Genotype data were available on 7085 SNPs from 23 to 53 MB on chromosome 12p11. Adjustment was made for vascular risk factors and population substructure using an additive genetic model. Subset analysis by WC was performed to test for a difference in genetic effects between the high and low WC subsets. RESULTS: In the overall analysis, the most significant association was found to rs10743465, downstream of the SOX5 gene (p = 1.27E-05). Also, 19 additional SNPs had nominal p < 0.001. In the subset analysis, the most significant difference in genetic effect between those with high and low WC occurred with rs1157480 (p = 1.37E-04 for the difference in ß coefficients), located upstream of TMTC1. Twelve additional SNPs in or near 6 genes had p < 0.001. CONCLUSIONS: The current study supports previously identified evidence by linkage for a genetic effect on LVM on chromosome 12p11 using association analysis in population-based Caribbean Hispanic cohort. SOX5 may play an important role in the regulation of LVM. An interaction of TMTC1 with abdominal obesity may contribute to phenotypic variation of LVM.
Assuntos
Cromossomos Humanos Par 12/genética , Estudos de Associação Genética/estatística & dados numéricos , Hipertrofia Ventricular Esquerda/genética , Idoso , Idoso de 80 Anos ou mais , República Dominicana , Feminino , Seguimentos , Ventrículos do Coração/patologia , Hispânico ou Latino/genética , Humanos , Hipertrofia Ventricular Esquerda/patologia , Escore Lod , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Obesidade Abdominal/genética , Tamanho do Órgão , Polimorfismo de Nucleotídeo Único/genética , Fatores de Transcrição SOXD/genética , Circunferência da CinturaRESUMO
BACKGROUND AND PURPOSE: Atherosclerosis is a complex subclinical cardiovascular disorder with a substantial genetic component. This study sought to identify genetic loci influencing carotid plaque in 2 independent samples. METHODS: B-mode ultrasound was performed to determine the presence and area of carotid plaque. Variance components analysis was used to test for linkage using 383 autosomal microsatellite markers in 1308 subjects from 100 Dominican families. Multiple linear and logistic regression models were used to investigate the association between plaque traits and 18,904 single nucleotide polymorphisms under the 1-logarithm of odds unit down regions of linkage peaks in an independent community-based data set (N = 941, 41% Dominicans) from the Northern Manhattan Study. RESULTS: After adjustment for age, hypertension, diabetes mellitus, cigarette pack-years, body mass index, and waist-to-hip ratio, significant heritability was detected for plaque presence (h² = 0.50 ± 0.14, P < 0.0001) and plaque area (h²=0.17 ± 0.04, P < 0.0001). Quantitative and dichotomous trait linkage analyses obtained similar results and identified 4 regions with multipoint logarithm of odds scores ≥ 2.00 on 7q36, 11p15, 14q32, and 15q23. In the association analysis of the 4 linkage peaks, several single nucleotide polymorphisms in or near SOX6, FSD2, AP3S2, EFTUD1, and MYOD1 were associated with carotid plaque traits with a nominal P ≤ 0.0005 in the Northern Manhattan Study data set and with a P ≤ 0.01 in Northern Manhattan Study Dominican subset. CONCLUSIONS: Carotid plaque has considerable heritability and may be influenced by loci on chromosomes 11p15, 14q32, and 15q23. The SOX6 gene within the bone morphogenic protein pathway could be a candidate for carotid plaque. Larger independent studies are needed to validate these findings.