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1.
PLoS One ; 15(8): e0236714, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32745108

RESUMO

BACKGROUND: A previous study suggested that intracranial aneurysms are more likely to occur in the same arterial territory within families. We aimed to replicate this analysis in independent families and in a sample limited to intracranial aneurysms that ruptured. METHODS: Among families with ≥2 first-degree relatives with intracranial aneurysms, we randomly matched index families to comparison families, and compared concordance in intracranial aneurysm territory between index and comparison families using a conditional logistic events/trials model. We analyzed three European cohorts separately, and pooled the results with those of the Familial Intracranial Aneurysm study by performing an inverse variance fixed effects meta-analysis. The main analysis included both unruptured and ruptured intracranial aneurysms, and a secondary analysis only ruptured intracranial aneurysms. RESULTS: Among 70 Dutch, 142 Finnish, and 34 French families, concordance regarding intracranial aneurysm territory was higher within families than between families, although not statistically significant. Meta-analysis revealed higher concordance in territory within families overall (odds ratio [OR] 1.7, 95%CI 1.3-2.2) and for each separate territory except the anterior cerebral artery. In the analysis of ruptured intracranial aneurysms, overall territory concordance was higher within families than between families (OR 1.8; 95%CI 1.1-2.7) but the territory-specific analysis showed statistical significance only for the internal carotid artery territory. CONCLUSIONS: We confirmed that familial intracranial aneurysms are more likely to occur in the same arterial territory within families. Moreover, we found that ruptured aneurysms were also more likely to occur in the same arterial territory within families.


Assuntos
Aneurisma Roto , Hereditariedade , Aneurisma Intracraniano , Aneurisma Roto/complicações , Aneurisma Roto/diagnóstico , Artéria Cerebral Anterior/patologia , Artéria Carótida Interna/patologia , Estudos de Coortes , Família , Feminino , Humanos , Aneurisma Intracraniano/complicações , Aneurisma Intracraniano/diagnóstico , Masculino , Razão de Chances , Fatores de Risco
2.
Nat Genet ; 52(8): 828-839, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32690947

RESUMO

The epigenome, including DNA methylation, is stably propagated during mitotic division. However, single-cell clonal expansion produces heterogeneous methylomes, thus raising the question of how the DNA methylome remains stable despite constant epigenetic drift. Here, we report that a clonal population of DNA (cytosine-5)-methyltransferase 1 (DNMT1)-only cells produces a heterogeneous methylome, which is robustly propagated on cell expansion and differentiation. Our data show that DNMT1 has imprecise maintenance activity and possibly possesses weak de novo activity, leading to spontaneous 'epimutations'. However, these epimutations tend to be corrected through a neighbor-guided mechanism, which is likely to be enabled by the environment-sensitive de novo activity ('tuner') and maintenance activity ('stabilizer') of DNMT1. By generating base-resolution maps of de novo and maintenance activities, we find that H3K9me2/3-marked regions show enhanced de novo activity, and CpG islands have both poor maintenance and de novo activities. The imprecise epigenetic machinery coupled with neighbor-guided correction may be a fundamental mechanism underlying robust yet flexible epigenetic inheritance.


Assuntos
DNA (Citosina-5-)-Metiltransferase 1/genética , Metilação de DNA/genética , Epigênese Genética/genética , Hereditariedade/genética , Animais , Células Cultivadas , Ilhas de CpG/genética , DNA/genética , Bases de Dados Genéticas , Epigenômica/métodos , Camundongos
3.
Am J Hum Genet ; 107(1): 158-163, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32516568

RESUMO

The discovery of genetic causes of inherited skin disorders has been pivotal to the understanding of epidermal differentiation, function, and renewal. Here we show via exome sequencing that mutations in ASPRV1 (aspartic peptidase retroviral-like 1) cause a dominant Mendelian disorder featuring palmoplantar keratoderma and lamellar ichthyosis, a phenotype that has otherwise been exclusively recessive. ASPRV1 encodes a mammalian-specific and stratified epithelia-specific protease important in processing of filaggrin, a critical component of the uppermost epidermal layer. Three different heterozygous ASPRV1 missense mutations in four unrelated ichthyosis kindreds segregate with disease and disrupt protein residues within close proximity to each other and autocatalytic cleavage sites. Expression of mutant ASPRV1 proteins demonstrates that all three mutations alter ASPRV1 auto-cleavage and filaggrin processing, a function vital to epidermal barrier integrity.


Assuntos
Hereditariedade/genética , Ictiose Lamelar/genética , Mutação de Sentido Incorreto/genética , Peptídeo Hidrolases/genética , Dermatopatias/genética , Heterozigoto , Humanos , Proteínas de Filamentos Intermediários/genética , Fenótipo , Sequenciamento Completo do Exoma/métodos
5.
Am J Surg Pathol ; 44(9): 1204-1212, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32520759

RESUMO

Hereditary diffuse gastric cancer (HDGC) is a rare autosomal dominant syndrome associated with an increased risk of developing Laurén's diffuse-type gastric carcinoma and lobular breast carcinoma. Although signet-ring cell carcinoma (SRCC) in situ (SRCC-pTis) has been reported as a characteristic lesion in HDGC cases with CDH1 germline mutations (CDH1 pathogenic variant), and a precursor of conventional intramucosal SRCC (SRCC-pT1a), its histopathologic features and specificity have not been sufficiently clarified. Here, we examined gastrectomy samples from 6 Japanese HDGC patients with CDH1 germline mutation, belonging to 4 families, and analyzed SRCC lesions histologically and immunohistochemically. Of the 274 foci found in the 6 samples, SRCC-pT1a accounted for 225 lesions (range: 8 to 107, mean 45.7 lesions per patient), while 46 foci were of SRCC-pTis (range: 1 to 15, mean 7.67 foci per patient). All SRCC-pTis foci were observed in the fundic gland area and on the superficial side of the mucosa. Histologically, tumor cells of SRCC-pTis were found between normal foveolar epithelial cells and the basement membrane, following a typical pagetoid spread pattern. Immunohistochemically, E-cadherin expression was lost in SRCC-pTis (27/28, 96.4%) more frequently than in SRCC-pT1a (95/197, 48.2%; P<0.001). To elucidate the specificity of SRCC-pTis for HDGC, 60 samples (range: 0.12 to 1.49 m, total 28.8 m of mucosal length) from gastric cancer cases were analyzed as controls, in which no SRCC-pTis were identified. Our results indicate that SRCC-pTis is a distinct histologic feature with high specificity for HDGC cases with CDH1 germline mutations.


Assuntos
Carcinoma de Células em Anel de Sinete/patologia , Síndromes Neoplásicas Hereditárias/patologia , Neoplasias Gástricas/patologia , Adulto , Antígenos CD/genética , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Caderinas/genética , Carcinoma de Células em Anel de Sinete/química , Carcinoma de Células em Anel de Sinete/genética , Carcinoma de Células em Anel de Sinete/cirurgia , Análise Mutacional de DNA , Feminino , Gastrectomia , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Hereditariedade , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/metabolismo , Síndromes Neoplásicas Hereditárias/cirurgia , Fenótipo , Estudos Retrospectivos , Neoplasias Gástricas/química , Neoplasias Gástricas/genética , Neoplasias Gástricas/cirurgia
6.
Nature ; 582(7811): 234-239, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32499652

RESUMO

On average, Peruvian individuals are among the shortest in the world1. Here we show that Native American ancestry is associated with reduced height in an ethnically diverse group of Peruvian individuals, and identify a population-specific, missense variant in the FBN1 gene (E1297G) that is significantly associated with lower height. Each copy of the minor allele (frequency of 4.7%) reduces height by 2.2 cm (4.4 cm in homozygous individuals). To our knowledge, this is the largest effect size known for a common height-associated variant. FBN1 encodes the extracellular matrix protein fibrillin 1, which is a major structural component of microfibrils. We observed less densely packed fibrillin-1-rich microfibrils with irregular edges in the skin of individuals who were homozygous for G1297 compared with individuals who were homozygous for E1297. Moreover, we show that the E1297G locus is under positive selection in non-African populations, and that the E1297 variant shows subtle evidence of positive selection specifically within the Peruvian population. This variant is also significantly more frequent in coastal Peruvian populations than in populations from the Andes or the Amazon, which suggests that short stature might be the result of adaptation to factors that are associated with the coastal environment in Peru.


Assuntos
Estatura/genética , Fibrilina-1/genética , Mutação de Sentido Incorreto , Seleção Genética , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Hereditariedade , Humanos , Índios Sul-Americanos/genética , Masculino , Microfibrilas/química , Microfibrilas/genética , Peru
7.
Nature ; 582(7811): 283-288, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32499657

RESUMO

Mobile genetic elements threaten genome integrity in all organisms. RDE-3 (also known as MUT-2) is a ribonucleotidyltransferase that is required for transposon silencing and RNA interference in Caenorhabditis elegans1-4. When tethered to RNAs in heterologous expression systems, RDE-3 can add long stretches of alternating non-templated uridine (U) and guanosine (G) ribonucleotides to the 3' termini of these RNAs (designated poly(UG) or pUG tails)5. Here we show that, in its natural context in C. elegans, RDE-3 adds pUG tails to targets of RNA interference, as well as to transposon RNAs. RNA fragments attached to pUG tails with more than 16 perfectly alternating 3' U and G nucleotides become gene-silencing agents. pUG tails promote gene silencing by recruiting RNA-dependent RNA polymerases, which use pUG-tailed RNAs (pUG RNAs) as templates to synthesize small interfering RNAs (siRNAs). Our results show that cycles of pUG RNA-templated siRNA synthesis and siRNA-directed pUG RNA biogenesis underlie double-stranded-RNA-directed transgenerational epigenetic inheritance in the C. elegans germline. We speculate that this pUG RNA-siRNA silencing loop enables parents to inoculate progeny against the expression of unwanted or parasitic genetic elements.


Assuntos
Caenorhabditis elegans/genética , Caenorhabditis elegans/parasitologia , Epigênese Genética/genética , Genoma/genética , Hereditariedade , Poli G/genética , Poli U/genética , RNA Mensageiro/genética , Animais , Caenorhabditis elegans/citologia , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Células Germinativas/citologia , Células Germinativas/metabolismo , Masculino , Nucleotidiltransferases/metabolismo , Interferência de RNA , RNA Replicase/metabolismo , RNA Interferente Pequeno/genética , Moldes Genéticos
8.
PLoS Genet ; 16(5): e1008798, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32469861

RESUMO

Alterations in epigenetic silencing have been associated with ageing and tumour formation. Although substantial efforts have been made towards understanding the mechanisms of gene silencing, novel regulators in this process remain to be identified. To systematically search for components governing epigenetic silencing, we developed a genome-wide silencing screen for yeast (Saccharomyces cerevisiae) silent mating type locus HMR. Unexpectedly, the screen identified the mismatch repair (MMR) components Pms1, Mlh1, and Msh2 as being required for silencing at this locus. We further found that the identified genes were also required for proper silencing in telomeres. More intriguingly, the MMR mutants caused a redistribution of Sir2 deacetylase, from silent mating type loci and telomeres to rDNA regions. As a consequence, acetylation levels at histone positions H3K14, H3K56, and H4K16 were increased at silent mating type loci and telomeres but were decreased in rDNA regions. Moreover, knockdown of MMR components in human HEK293T cells increased subtelomeric DUX4 gene expression. Our work reveals that MMR components are required for stable inheritance of gene silencing patterns and establishes a link between the MMR machinery and the control of epigenetic silencing.


Assuntos
Proteína 1 Homóloga a MutL/genética , Proteínas MutL/genética , Proteína 2 Homóloga a MutS/genética , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Acetilação , Reparo de Erro de Pareamento de DNA , Epigênese Genética , Inativação Gênica , Genes Fúngicos Tipo Acasalamento , Hereditariedade , Histonas/metabolismo , Saccharomyces cerevisiae/genética , Proteínas Reguladoras de Informação Silenciosa de Saccharomyces cerevisiae/metabolismo , Sirtuína 2/metabolismo , Telômero/genética
9.
Mol Cell ; 78(3): 371-373, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32386538

RESUMO

Yoshida et al. (2020) report in this issue of Molecular Cell that a paternal low-protein diet elevates ROS in the testicular germ cells, altering ATF7 activity and H3K9me2 abundance on target genes, including tRNA loci. These changes are maintained in spermatozoa, regulating tsRNA biogenesis, and together transmit intergenerational effects.


Assuntos
Dieta com Restrição de Proteínas , Hereditariedade , Epigênese Genética , Masculino , Espécies Reativas de Oxigênio , Espermatozoides
10.
Thromb Haemost ; 120(5): 758-767, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32369847

RESUMO

BACKGROUND: Ligneous conjunctivitis (LC) is a rare disorder associated with plasminogen deficiency characterized by chronic fibrin deposits in the eyelids. All patients with plasminogen deficiency do not develop LC, whose underlying mechanisms remain unknown. OBJECTIVE: We investigated whether fibrinolytic activity was correlated with phenotype and/or genotype in patients suffering from LC and their relatives. METHODS: Plasminogen activity/antigen levels and PLG mutations were determined in 10 patients with LC, 17 of their asymptomatic relatives, and 10 healthy individuals used as a control group. Plasma fibrinolytic activity was evaluated using three different assays: (1) tissue-plasminogen activator (t-PA) front lysis, (2) cell-based urokinase-dependent euglobulin clot lysis (ECLT) at the surface of corneal cells, and (3) urokinase-dependent plasminogen activation. RESULTS: Plasminogen activity varied from <10 to 40% in patients, 36 to 105% in relatives, and >80% in control healthy individuals. Homozygous K19E mutation was associated with normal antigenic plasminogen levels. In front-lysis experiments, all patients had a lower fibrinolysis rate as compared with their relatives and to control individuals. The cell-based ECLT and plasminogen activation assay demonstrated that urokinase-mediated fibrinolysis was not impaired in patients with homozygous K19E mutation compared with the other mutants. CONCLUSION: We confirm that plasminogen levels fail to predict LC occurrence. In these conditions, t-PA clot lysis front is useful to predict clinical outcome in plasminogen deficiency. Moreover, we provide evidence that occurrence of LC overlaps quantitative and qualitative plasminogen deficiencies. The homozygous K19E mutation is associated with isolated impaired t-PA-mediated fibrinolysis compared with other mutants.


Assuntos
Testes de Coagulação Sanguínea , Conjuntivite/diagnóstico , Olho/metabolismo , Fibrina/metabolismo , Fibrinólise , Plasminogênio/deficiência , Dermatopatias Genéticas/diagnóstico , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Conjuntivite/genética , Conjuntivite/metabolismo , Feminino , Predisposição Genética para Doença , Hereditariedade , Heterozigoto , Homozigoto , Humanos , Cinética , Masculino , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Mutação , Linhagem , Fenótipo , Plasminogênio/genética , Plasminogênio/metabolismo , Valor Preditivo dos Testes , Dermatopatias Genéticas/genética , Dermatopatias Genéticas/metabolismo , Ativador de Plasminogênio Tecidual/metabolismo , Adulto Jovem
11.
J Stroke Cerebrovasc Dis ; 29(7): 104803, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32387185

RESUMO

Autosomal dominant cerebral arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL), is a genetic disease caused by mutations in the Notch3 gene. More than 170 monogenic mutations leading to the development of CADASIL have been reported. We describe a case of a patient and her family with compatible symptoms of CADASIL disease, in which a variable not yet described in the Notch3 gene was detected, that generates a probably pathogenic change in the protein.


Assuntos
CADASIL/genética , Mutação , Receptor Notch3/genética , Adulto , CADASIL/diagnóstico por imagem , CADASIL/fisiopatologia , CADASIL/psicologia , Feminino , Predisposição Genética para Doença , Hereditariedade , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo
12.
J Stroke Cerebrovasc Dis ; 29(7): 104832, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32414585

RESUMO

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL; OMIM #125310) is the most common cause of monogenic familial cerebral small vessel disease. It typically manifests at middle adulthood with highly variable clinical features including migraine with aura, recurrent transient ischemic attacks or ischemic strokes, mood disorders, and progressive cognitive decline. It is caused by mutations in the NOTCH3 gene, which maps to the short arm of chromosome 19 and encode for epidermal growth factor-like repeats. In this article, we report a 40-year-old male patient who presented with a two-year history of progressive cognitive decline including impaired attention, memory, executive functions, and processing speed whose family history was strongly positive for young-onset ischemic stroke and memory impairment. His father, uncle, and grandfather died due to ischemic strokes and cognitive impairment (similar condition). A whole exome sequencing to the patient (proband II-1) revealed a novel heterozygous missense variant c.3009G>T, p.(Trp1003Cys) (chr19;15291625; hg19) in exon 19 of the NOTCH3 gene. Sanger sequencing was used to confirm the variant in other family members. This variant has not been described in the literature so far. The novel mutation described in the present study widened the genetic spectrum of NOTCH3-associated diseases, which will benefit studies addressing this disease in the future. CADASIL remains a disabling disorder leading to medical retirement in our patient due to late clinical presentation, lack of family history taking prior to joining the military, and lack of curative therapy. Further research for therapeutic options is needed including stem cell therapy .


Assuntos
CADASIL/genética , Mutação de Sentido Incorreto , Receptor Notch3/genética , Adulto , CADASIL/diagnóstico por imagem , CADASIL/fisiopatologia , CADASIL/terapia , Análise Mutacional de DNA , Éxons , Predisposição Genética para Doença , Hereditariedade , Heterozigoto , Humanos , Imagem por Ressonância Magnética , Masculino , Linhagem , Fenótipo , Arábia Saudita , Sequenciamento Completo do Exoma
13.
Mol Cell ; 78(5): 915-925.e7, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32392469

RESUMO

Transcriptional memory of gene expression enables adaptation to repeated stimuli across many organisms. However, the regulation and heritability of transcriptional memory in single cells and through divisions remains poorly understood. Here, we combined microfluidics with single-cell live imaging to monitor Saccharomyces cerevisiae galactokinase 1 (GAL1) expression over multiple generations. By applying pedigree analysis, we dissected and quantified the maintenance and inheritance of transcriptional reinduction memory in individual cells through multiple divisions. We systematically screened for loss- and gain-of-memory knockouts to identify memory regulators in thousands of single cells. We identified new loss-of-memory mutants, which affect memory inheritance into progeny. We also unveiled a gain-of-memory mutant, elp6Δ, and suggest that this new phenotype can be mediated through decreased histone occupancy at the GAL1 promoter. Our work uncovers principles of maintenance and inheritance of gene expression states and their regulators at the single-cell level.


Assuntos
Galactoquinase/genética , Regulação Fúngica da Expressão Gênica/genética , Transcrição Genética/genética , Galactose/metabolismo , Expressão Gênica/genética , Genes Fúngicos/genética , Hereditariedade/genética , Histonas/metabolismo , Regiões Promotoras Genéticas/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Análise de Célula Única/métodos
15.
Open Heart ; 7(1): e001143, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32257244

RESUMO

Objective: Morbidity and mortality due to heart failure (HF) as a complication of myocardial infarction (MI) is high, and remains among the leading causes of death and hospitalisation. This study investigated the association between family history of MI with or without HF, and the risk of developing HF after first MI. Methods: Through nationwide registries, we identified all individuals aged 18-50 years hospitalised with first MI from 1997 to 2016 in Denmark. We identified 13 810 patients with MI, and the cohort was followed until HF diagnosis, second MI, 3 years after index MI, emigration, death or the end of 2016, whichever occurred first. HRs were estimated by Cox hazard regression models adjusted for sex, age, calendar year and comorbidities (reference: patients with no family history of MI). Results: After adjustment, we observed an increased risk of MI-induced HF for those having a sibling with MI with HF (HR 2.05, 95% CI 1.02 to 4.12). Those having a sibling with MI without HF also had a significant, but lower increased risk of HF (HR 1.39, 95% CI 1.05 to 1.84). Parental history of MI with or without HF was not associated with HF. Conclusion: In this nationwide cohort, sibling history of MI with or without HF was associated with increased risk of HF after first MI, while a parental family history was not, suggesting that shared environmental factors may predominate in the determination of risk for developing HF.


Assuntos
Insuficiência Cardíaca/epidemiologia , Infarto do Miocárdio/epidemiologia , Irmãos , Adolescente , Adulto , Idade de Início , Comorbidade , Dinamarca/epidemiologia , Meio Ambiente , Feminino , Predisposição Genética para Doença , Nível de Saúde , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/genética , Hereditariedade , Humanos , Masculino , Anamnese , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/genética , Pais , Linhagem , Sistema de Registros , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Adulto Jovem
16.
Open Heart ; 7(1): e001220, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32341788

RESUMO

Objective: The myosin-binding protein C (MYBPC3) c.927-2A>G founder mutation accounts for >90% of sarcomeric hypertrophic cardiomyopathy (HCM) in Iceland. This cross-sectional observational study explored the penetrance and phenotypic burden among carriers of this single, prevalent founder mutation. Methods: We studied 60 probands with HCM caused by MYBPC3 c.927-2A>G and 225 first-degree relatives. All participants underwent comprehensive clinical evaluation and relatives were genotyped. Results: Genetic and clinical evaluation of relatives identified 49 genotype-positive (G+) relatives with left ventricular hypertrophy (G+/LVH+), 59 G+without LVH (G+/LVH-) and 117 genotype-negative relatives (unaffected). Compared with HCM probands, G+/LVH+ relatives were older at HCM diagnosis, had less LVH, a less prevalent diastolic dysfunction, fewer ECG abnormalities, lower serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I levels, and fewer symptoms. The penetrance of HCM was influenced by age and sex; specifically, LVH was present in 39% of G+males but only 9% of G+females under age 40 years (p=0.015), versus 86% and 83%, respectively, after age 60 (p=0.89). G+/LVH- subjects had normal wall thicknesses, diastolic function and NT-proBNP levels, but subtle changes in LV geometry and more ECG abnormalities than their unaffected relatives. Conclusions: Phenotypic expression of the Icelandic MYBPC3 founder mutation varies by age, sex and proband status. Men are more likely to have LVH at a younger age, and disease manifestations were more prominent in probands than in relatives identified via family screening. G+/LVH- individuals had subtle clinical differences from unaffected relatives well into adulthood, indicating subclinical phenotypic expression of the pathogenic mutation.


Assuntos
Cardiomiopatia Hipertrófica/genética , Proteínas de Transporte/genética , Efeito Fundador , Heterozigoto , Mutação , Sarcômeros/genética , Função Ventricular Esquerda/genética , Remodelação Ventricular/genética , Adulto , Idade de Início , Idoso , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/fisiopatologia , Estudos Transversais , Feminino , Predisposição Genética para Doença , Hemodinâmica/genética , Hereditariedade , Humanos , Islândia , Masculino , Pessoa de Meia-Idade , Linhagem , Penetrância , Fenótipo , Fatores de Risco
17.
Arterioscler Thromb Vasc Biol ; 40(5): 1392-1399, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32160777

RESUMO

OBJECTIVE: Venous thrombosis (VT) is a complex condition with a highly heritable genetic component that predisposes one to its development. Certain microRNAs (miRNAs) might be used as biomarkers of VT, but few studies have examined miRNA expression in this respect. The aim of the present work was to identify a plasma miRNA profile associated with VT. Approach and Results: miRNAs were analyzed by quantitative polymerase chain reaction in plasma samples from members of the GAIT-2 (Genetic Analysis of Idiopathic Thrombophilia 2) population (n=935). A discovery phase involving the screening of 752 miRNAs from a subset of 104 GAIT-2 subjects was followed by an internal validation phase in which the selected miRNAs were quantified in the whole GAIT-2 population. In the discovery phase, 16 miRNAs were selected, including 9 associated with VT and 7 that correlated with an intermediate phenotype of VT. In the next phase, 4 miRNAs were validated as differentially expressed (false discovery rate, <0.1) in VT: hsa-miR-126-3p, hsa-miR-885-5p, hsa-miR-194-5p, and hsa-miR-192-5p. The 4 miRNAs each returned a significant (P<0.05) odds ratio for VT (range of 1.3-1.8). A risk model including the 4 miRNAs, age, and sex returned an area under the receiver operating characteristic curve of 0.77. Moreover, all 4 miRNAs showed significant correlations with intermediate phenotypes of VT (eg, protein S and factor VII). The targets of the miRNAs in the blood coagulation pathway and their interactions are also discussed. CONCLUSIONS: The present results suggest a 4-miRNA plasma profile associated with VT is of potential use in predicting the risk of this condition.


Assuntos
Coagulação Sanguínea/genética , MicroRNA Circulante/genética , Perfilação da Expressão Gênica/métodos , Reação em Cadeia da Polimerase , Transcriptoma , Trombose Venosa/genética , Estudos de Casos e Controles , MicroRNA Circulante/sangue , Predisposição Genética para Doença , Hereditariedade , Humanos , Fenótipo , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Espanha , Trombose Venosa/sangue , Trombose Venosa/diagnóstico
18.
Prog Cardiovasc Dis ; 63(3): 308-326, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32201287

RESUMO

Floppy mitral valve/mitral valve prolapse (FMV/MVP) is a common valvular abnormality affecting 2% to 3% of the general population. It occurs in a heterogeneous group of patients with varying and age dependent expressions. FMV/MVP can be familial or sporadic, isolated (called non-syndromic) or as a part of a well-defined syndrome of heritable connective tissue disorders or other diseases. A wide range of phenotypic expression exists ranging from asymptomatic to non-specific symptoms related to neuroendocrine or autonomic nervous system functional abnormalities, varying degrees of mitral regurgitation that may require interventional therapy, heart failure, infective endocarditis, cardiac arrhythmias and/or sudden cardiac death. FMV/MVP is predominantly considered a heritable disorder with clinical manifestations not present at birth, but appearing later in life. Though a variant gene may initiate the development of FMV/MVP, precise phenotypic expression may be related to multiple other molecular, genetic and epigenetic factors that modify the final expression of the disease. A better understanding of these mechanisms will help to better define the natural history of the disease, inhibit disease progression and even prevent the phenotypic expression of FMV/MVP.


Assuntos
Prolapso da Valva Mitral/genética , Valva Mitral/anormalidades , Progressão da Doença , Predisposição Genética para Doença , Hereditariedade , Humanos , Valva Mitral/fisiopatologia , Prolapso da Valva Mitral/epidemiologia , Prolapso da Valva Mitral/fisiopatologia , Prolapso da Valva Mitral/terapia , Linhagem , Fenótipo , Prevalência , Fatores de Risco
19.
Hum Pathol ; 98: 64-73, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32088208

RESUMO

Juvenile papillomatosis (JP), the so-called Swiss cheese disease, is a rare benign breast disease of young adults. An association (up to 28%) with breast cancer within the family of affected patients has been reported. A multinodular cystic breast mass lesion and calcifications characterizes JP in imaging studies. The histological picture is diverse and comprises multiple intraductal papillomas, usual ductal hyperplasia, ductectasias, perifocal sclerosing adenosis, and calcification. Patients with complete excision of JP lesions have an excellent follow-up; breast cancer develops only on a very low subset of patients. Molecular background of JP has not been investigated until now. In this study, we addressed mutational analysis of JP cases and correlated these results with follow-up and family history in context with a comprehensive review of the JP literature. We identified 13 cases fulfilling the criteria of JP. All patients were women with a median age of 38 years (26-50 years). Follow-up information was available for 11 of 13 patients. Sufficient paraffin-embedded tissue and good DNA quality for next-generation sequencing (NGS) was available for 10 patients. Paraffin blocks were microdissected in the area of intraductal proliferative disease; the tissue cores underwent NGS analysis using the Oncomine Comprehensive Panel. In 5 of 10 patients, we found PIK3CA mutations; in 2 of 10 patients, we found AKT1 mutations in known hot spot regions. Further mutations in MET, FGFR3, PTEN, ATM, NF1, and GNAS genes were detected in individual patients. Some of these mutations were present at high allele frequencies suggesting germ line mutations. Two of 3 patients with positive family history had PIK3CA mutation; one patient with positive family history had an AKT1 mutation. One patient who subsequently developed invasive ductal carcinoma in the contralateral breast possibly had a germ line ATM mutation. Our results confirm hot spot mutations in PIK3CA and AKT1 genes in JP associated with positive family history for breast cancer, although these mutations are not specific for JP. The genetic link between JP, positive family history, and subsequent risk of breast cancer needs to be analyzed in further studies.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Mutação , Papiloma/genética , Proteínas Proto-Oncogênicas c-akt/genética , Adulto , Idade de Início , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Hereditariedade , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-Idade , Papiloma/patologia , Papiloma/cirurgia , Linhagem , Fenótipo
20.
Poult Sci ; 99(2): 702-707, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32036974

RESUMO

Improving the digestive efficiency of birds is becoming increasingly important with the diversification of feedstuffs used in poultry diets. Compared with time-consuming chemical analyses that were previously used to measure digestive efficiency, near-infrared spectroscopy has been a great advance as it was fast and thus allowed measurements to be taken from a large number of animals, as required for genetic studies. However, it still implies to rear the birds in cages to collect feces, which is questionable in terms of welfare. The purpose of this study was thus to establish whether the serum color could be used as a biomarker of digestive efficiency that would be easy and fast to measure on floor-reared animals. We first compared the serum color of 2 lines of chickens divergently selected for high or low digestive efficiency when fed with a wheat-based diet. Digestive efficiency was assessed by nitrogen-corrected apparent metabolizable energy. Color was assessed by the absorbance of the serum between 300 and 572 nm. Color differed between the 2 lines between 430 and 572 nm, which corresponds to the absorption zone of carotenoids such as lutein and zeaxanthin. In a second step, we estimated the heritability of serum color measurements and their genetic correlations with digestive efficiency. Taking these parameters into account, in our experimental conditions the best trait among those tested that can be used as a biomarker of digestive efficiency is serum absorbance at 492 nm, with a heritability estimate of 0.31 ± 0.09 and a genetic correlation with digestive efficiency of 0.84 ± 0.28.


Assuntos
Criação de Animais Domésticos/métodos , Galinhas/fisiologia , Digestão , Soro/química , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Biomarcadores/sangue , Galinhas/genética , Cor , Dieta/veterinária , Feminino , Hereditariedade , Masculino , Fenótipo , Seleção Genética
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