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1.
Am J Hum Genet ; 107(4): 654-669, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32937144

RESUMO

There is growing recognition that epivariations, most often recognized as promoter hypermethylation events that lead to gene silencing, are associated with a number of human diseases. However, little information exists on the prevalence and distribution of rare epigenetic variation in the human population. In order to address this, we performed a survey of methylation profiles from 23,116 individuals using the Illumina 450k array. Using a robust outlier approach, we identified 4,452 unique autosomal epivariations, including potentially inactivating promoter methylation events at 384 genes linked to human disease. For example, we observed promoter hypermethylation of BRCA1 and LDLR at population frequencies of ∼1 in 3,000 and ∼1 in 6,000, respectively, suggesting that epivariations may underlie a fraction of human disease which would be missed by purely sequence-based approaches. Using expression data, we confirmed that many epivariations are associated with outlier gene expression. Analysis of variation data and monozygous twin pairs suggests that approximately two-thirds of epivariations segregate in the population secondary to underlying sequence mutations, while one-third are likely sporadic events that occur post-zygotically. We identified 25 loci where rare hypermethylation coincided with the presence of an unstable CGG tandem repeat, validated the presence of CGG expansions at several loci, and identified the putative molecular defect underlying most of the known folate-sensitive fragile sites in the genome. Our study provides a catalog of rare epigenetic changes in the human genome, gives insight into the underlying origins and consequences of epivariations, and identifies many hypermethylated CGG repeat expansions.


Assuntos
Proteína BRCA1/genética , Epigênese Genética , Doenças Genéticas Inatas/genética , Genoma Humano , Receptores de LDL/genética , Expansão das Repetições de Trinucleotídeos , Proteína BRCA1/metabolismo , Metilação de DNA , Feminino , Ácido Fólico/metabolismo , Inativação Gênica , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/patologia , Loci Gênicos , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Regiões Promotoras Genéticas , Receptores de LDL/metabolismo , Gêmeos Monozigóticos
2.
Am J Hum Genet ; 107(3): 418-431, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32758451

RESUMO

While genome-wide association studies have identified susceptibility variants for numerous traits, their combined utility for predicting broad measures of health, such as mortality, remains poorly understood. We used data from the UK Biobank to combine polygenic risk scores (PRS) for 13 diseases and 12 mortality risk factors into sex-specific composite PRS (cPRS). These cPRS were moderately associated with all-cause mortality in independent data within the UK Biobank: the estimated hazard ratios per standard deviation were 1.10 (95% confidence interval: 1.05, 1.16) and 1.15 (1.10, 1.19) for women and men, respectively. Differences in life expectancy between the top and bottom 5% of the cPRS were estimated to be 4.79 (1.76, 7.81) years and 6.75 (4.16, 9.35) years for women and men, respectively. These associations were substantially attenuated after adjusting for non-genetic mortality risk factors measured at study entry (i.e., middle age for most participants). The cPRS may be useful in counseling younger individuals at higher genetic risk of mortality on modification of non-genetic factors.


Assuntos
Doenças Genéticas Inatas/mortalidade , Predisposição Genética para Doença , Herança Multifatorial/genética , Medição de Risco/estatística & dados numéricos , Bancos de Espécimes Biológicos , Feminino , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Modelos de Riscos Proporcionais , Fatores de Risco , Reino Unido
3.
Nat Rev Mol Cell Biol ; 21(10): 571-584, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32636524

RESUMO

The historical reliance of biological research on the use of animal models has sometimes made it challenging to address questions that are specific to the understanding of human biology and disease. But with the advent of human organoids - which are stem cell-derived 3D culture systems - it is now possible to re-create the architecture and physiology of human organs in remarkable detail. Human organoids provide unique opportunities for the study of human disease and complement animal models. Human organoids have been used to study infectious diseases, genetic disorders and cancers through the genetic engineering of human stem cells, as well as directly when organoids are generated from patient biopsy samples. This Review discusses the applications, advantages and disadvantages of human organoids as models of development and disease and outlines the challenges that have to be overcome for organoids to be able to substantially reduce the need for animal experiments.


Assuntos
Biologia/métodos , Medicina/métodos , Organoides/fisiologia , Animais , Doenças Transmissíveis/patologia , Doenças Genéticas Inatas/patologia , Engenharia Genética/métodos , Humanos , Neoplasias/patologia , Células-Tronco/fisiologia
4.
Mol Cell ; 79(3): 504-520.e9, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32707033

RESUMO

Protein kinases are essential for signal transduction and control of most cellular processes, including metabolism, membrane transport, motility, and cell cycle. Despite the critical role of kinases in cells and their strong association with diseases, good coverage of their interactions is available for only a fraction of the 535 human kinases. Here, we present a comprehensive mass-spectrometry-based analysis of a human kinase interaction network covering more than 300 kinases. The interaction dataset is a high-quality resource with more than 5,000 previously unreported interactions. We extensively characterized the obtained network and were able to identify previously described, as well as predict new, kinase functional associations, including those of the less well-studied kinases PIM3 and protein O-mannose kinase (POMK). Importantly, the presented interaction map is a valuable resource for assisting biomedical studies. We uncover dozens of kinase-disease associations spanning from genetic disorders to complex diseases, including cancer.


Assuntos
Redes Reguladoras de Genes , Doenças Genéticas Inatas/genética , Neoplasias/genética , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Biologia Computacional/métodos , Conjuntos de Dados como Assunto , Regulação da Expressão Gênica , Ontologia Genética , Doenças Genéticas Inatas/enzimologia , Doenças Genéticas Inatas/patologia , Humanos , Redes e Vias Metabólicas/genética , Anotação de Sequência Molecular , Distrofias Musculares/enzimologia , Distrofias Musculares/genética , Distrofias Musculares/patologia , Neoplasias/enzimologia , Neoplasias/patologia , Doenças Neurodegenerativas/enzimologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Mapeamento de Interação de Proteínas/métodos , Proteínas Quinases/química , Proteínas Quinases/classificação , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/química , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais
5.
Hum Genet ; 139(6-7): 769-776, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32405658

RESUMO

Over the last decade next generation sequencing (NGS) has been extensively used to identify new pathogenic mutations and genes causing rare genetic diseases. The efficient analyses of NGS data is not trivial and requires a technically and biologically rigorous pipeline that addresses data quality control, accurate variant filtration to minimize false positives and false negatives, and prioritization of the remaining genes based on disease genomics and physiological knowledge. This review provides a pipeline including all these steps, describes popular software for each step of the analysis, and proposes a general framework for the identification of causal mutations and genes in individual patients of rare genetic diseases.


Assuntos
Biologia Computacional/métodos , Genes/genética , Doenças Genéticas Inatas/etiologia , Genoma Humano , Mutação , Medicina de Precisão , Doenças Raras/etiologia , Doenças Genéticas Inatas/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Doenças Raras/patologia , Software
6.
Rinsho Shinkeigaku ; 60(5): 334-339, 2020 May 26.
Artigo em Japonês | MEDLINE | ID: mdl-32307395

RESUMO

Hereditary myopathy with early respiratory failure (HMERF) with heterozygous mutations in the titin gene (TTN) is characterized by respiratory failure developing from the early phase of limb weakness or gait disturbance. Here, we describe a characteristic distribution of muscle involvement in three members of a HMERF family with a TTN mutation. Despite the differences in severity exhibited among the father, daughter and son, the systemic imaging studies showed a similar pattern among these individuals. The semitendinosus and fibularis longus muscles were selectively affected, as described previously. In addition, we found marked atrophy in the sternocleidomastoid and psoas major muscles, regardless of the disease severity. The atrophy in selective trunk muscles observed in routine CT scans can be useful for the differential diagnosis of hereditary myopathies with heart and respiratory failure.


Assuntos
Conectina/genética , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Músculo Esquelético/patologia , Doenças Musculares/genética , Doenças Musculares/patologia , Mutação , Insuficiência Respiratória/genética , Insuficiência Respiratória/patologia , Adulto , Idoso , Atrofia , Diagnóstico Diferencial , Feminino , Doenças Genéticas Inatas/diagnóstico por imagem , Humanos , Masculino , Músculo Esquelético/diagnóstico por imagem , Doenças Musculares/diagnóstico por imagem , Insuficiência Respiratória/diagnóstico por imagem , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X
7.
PLoS One ; 15(3): e0225901, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32119674

RESUMO

Hereditary nasal parakeratosis (HNPK) is an inherited disorder described in Labrador Retrievers and Greyhounds. It has been associated with breed-specific variants in the SUV39H2 gene encoding a histone 3 methyltransferase involved in epigenetic silencing. Formalin-fixed biopsies of the nasal planum of Labrador Retrievers were screened by immunofluorescence microscopy for the presence and distribution of epidermal proliferation and differentiation markers. Gene expression of these markers was further analysed using RNA sequencing (RNA-seq) and ultrastructural epidermal differences were investigated by electron microscopy. Differentiation of the nasal planum in the basal and suprabasal epidermal layers of HNPK-affected dogs (n = 6) was similar compared to control dogs (n = 6). In the upper epidermal layers, clear modifications were noticed. Loricrin protein was absent in HNPK-affected nasal planum sections in contrast to sections of the same location of control dogs. However, loricrin was present in the epidermis of paw pads and abdominal skin from HNPK dogs and healthy control dogs. The patterns of keratins K1, K10 and K14, were not markedly altered in the nasal planum of HNPK-affected dogs while the expression of the terminal differentiation marker involucrin appeared less regular. Based on RNA-seq, LOR and IVL expression levels were significantly decreased, while KRT1, KRT10 and KRT14 levels were up-regulated (log2fold-changes of 2.67, 3.19 and 1.71, respectively) in HNPK-affected nasal planum (n = 3) compared to control dogs (n = 3). Electron microscopical analysis revealed structural alterations in keratinocytes and stratum corneum, and disrupted keratinocyte adhesions and distended intercellular spaces in lesional samples (n = 3) compared to a sample of a healthy control dog (n = 1). Our findings demonstrate aberrant keratinocyte terminal differentiation of the nasal planum of HNPK-affected Labrador Retrievers and provide insights into biological consequences of this inactive SUV39H2 gene variant.


Assuntos
Antígenos de Diferenciação , Doenças do Cão , Doenças Genéticas Inatas , Doenças Nasais , Paraceratose , Animais , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/metabolismo , Doenças do Cão/genética , Doenças do Cão/metabolismo , Doenças do Cão/patologia , Cães , Feminino , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/metabolismo , Doenças Genéticas Inatas/patologia , Doenças Genéticas Inatas/veterinária , Queratinócitos/metabolismo , Queratinócitos/patologia , Masculino , Doenças Nasais/genética , Doenças Nasais/metabolismo , Doenças Nasais/patologia , Doenças Nasais/veterinária , Paraceratose/genética , Paraceratose/metabolismo , Paraceratose/patologia , Paraceratose/veterinária
8.
Hum Reprod Update ; 26(2): 197-213, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32068234

RESUMO

BACKGROUND: Human reproductive issues affecting fetal and maternal health are caused by numerous exogenous and endogenous factors, of which the latter undoubtedly include genetic changes. Pathogenic variants in either maternal or offspring DNA are associated with effects on the offspring including clinical disorders and nonviable outcomes. Conversely, both fetal and maternal factors can affect maternal health during pregnancy. Recently, it has become evident that mammalian reproduction is influenced by genomic imprinting, an epigenetic phenomenon that regulates the expression of genes according to their parent from whom they are inherited. About 1% of human genes are normally expressed from only the maternally or paternally inherited gene copy. Since numerous imprinted genes are involved in (embryonic) growth and development, disturbance of their balanced expression can adversely affect these processes. OBJECTIVE AND RATIONALE: This review summarises current our understanding of genomic imprinting in relation to human ontogenesis and pregnancy and its relevance for reproductive medicine. SEARCH METHODS: Literature databases (Pubmed, Medline) were thoroughly searched for the role of imprinting in human reproductive failure. In particular, the terms 'multilocus imprinting disturbances, SCMC, NLRP/NALP, imprinting and reproduction' were used in various combinations. OUTCOMES: A range of molecular changes to specific groups of imprinted genes are associated with imprinting disorders, i.e. syndromes with recognisable clinical features including distinctive prenatal features. Whereas the majority of affected individuals exhibit alterations at single imprinted loci, some have multi-locus imprinting disturbances (MLID) with less predictable clinical features. Imprinting disturbances are also seen in some nonviable pregnancy outcomes, such as (recurrent) hydatidiform moles, which can therefore be regarded as a severe form of imprinting disorders. There is growing evidence that MLID can be caused by variants in the maternal genome altering the imprinting status of the oocyte and the embryo, i.e. maternal effect mutations. Pregnancies of women carrying maternal affect mutations can have different courses, ranging from miscarriages to birth of children with clinical features of various imprinting disorders. WIDER IMPLICATIONS: Increasing understanding of imprinting disturbances and their clinical consequences have significant impacts on diagnostics, counselling and management in the context of human reproduction. Defining criteria for identifying pregnancies complicated by imprinting disorders facilitates early diagnosis and personalised management of both the mother and offspring. Identifying the molecular lesions underlying imprinting disturbances (e.g. maternal effect mutations) allows targeted counselling of the family and focused medical care in further pregnancies.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/etiologia , Impressão Genômica/fisiologia , Resultado da Gravidez/genética , Reprodução/genética , Animais , Feminino , Doenças Genéticas Inatas/patologia , Humanos , Masculino , Mutação/fisiologia , Gravidez , Prognóstico
9.
J Clin Invest ; 130(2): 921-926, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31929190

RESUMO

Risk for childhood asthma is conferred by alleles within the 17q21 locus affecting ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) expression. ORMDL3 inhibits sphingolipid de novo synthesis. Although the effects of 17q21 genotypes on sphingolipid synthesis in human asthma remain unclear, both decreased sphingolipid synthesis and ORMDL3 overexpression are linked to airway hyperreactivity. To characterize the relationship of genetic asthma susceptibility with sphingolipid synthesis, we analyzed asthma-associated 17q21 genotypes (rs7216389, rs8076131, rs4065275, rs12603332, and rs8067378) in both children with asthma and those without asthma, quantified plasma and whole-blood sphingolipids, and assessed sphingolipid de novo synthesis in peripheral blood cells by measuring the incorporation of stable isotope-labeled serine (substrate) into sphinganine and sphinganine-1-phosphate. Whole-blood dihydroceramides and ceramides were decreased in subjects with the 17q21 asthma-risk alleles rs7216389 and rs8076131. Children with nonallergic asthma had lower dihydroceramides, ceramides, and sphingomyelins than did controls. Children with allergic asthma had higher dihydroceramides, ceramides, and sphingomyelins compared with children with nonallergic asthma. Additionally, de novo sphingolipid synthesis was lower in children with asthma compared with controls. These findings connect genetic 17q21 variations that are associated with asthma risk and higher ORMDL3 expression to lower sphingolipid synthesis in humans. Altered sphingolipid synthesis may therefore be a critical factor in asthma pathogenesis and may guide the development of future therapeutics.


Assuntos
Asma , Cromossomos Humanos Par 17 , Doenças Genéticas Inatas , Proteínas de Membrana , Esfingolipídeos/biossíntese , Adolescente , Asma/sangue , Asma/genética , Asma/patologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 17/metabolismo , Feminino , Doenças Genéticas Inatas/sangue , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Humanos , Masculino , Proteínas de Membrana/sangue , Proteínas de Membrana/genética , Fatores de Risco
10.
Mol Med Rep ; 21(3): 1115-1124, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31922211

RESUMO

Hereditary nephropathy is a progressive fatal renal disease caused by genetic changes. In this study, genetic screening was used to reveal mutations in a family in Southern China, in which there are two patients with confirmed hereditary nephropathy, who are alive at the time of publication. Imaging tests, including color Doppler ultrasonography and magnetic resonance imaging (MRI), as well as pathological examinations, including hematoxylin­eosin staining, electron microscopy and immunohistochemistry were performed. Target sequencing of nephrosis 2 (NPHS2), wilms tumor 1 (WT1), phospholipase C ε 1 (PLCE1), actinin α 4 (ACTN4), angiotensin I converting enzyme (ACE), uromodulin (UMOD) and nephrocystin 1 (NPHP1) was also carried out. This study indicated that heterozygous genetic variants of NPHS2, WT1, ACTN4, PLCE1 and UMOD found in the patients were gene polymorphisms. A renal biopsy showed sclerosing glomerulonephritis, dilated tubules and lymphocyte/monocyte infiltration in the interstitium of the index patients. Genetic analysis showed vertical transmission of the disease­causing mutations, including a homozygous deletion in NPHP1 and a nonsense mutation in ACE found via PCR­based single nucleotide polymorphism screening. Further network analysis identified direct and indirect co­location genes between NPHP1 and ACE. To conclude, familial adolescent nephronophthisis was diagnosed in two index patients in this study. It is recommended that comprehensive gene mutation screening is used in the diagnosis of complex hereditary diseases.


Assuntos
Família , Doenças Genéticas Inatas , Glomerulonefrite , Doenças Renais Císticas , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático , China , Feminino , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Glomerulonefrite/genética , Glomerulonefrite/patologia , Humanos , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Masculino , Pessoa de Meia-Idade
11.
J Biosci ; 452020.
Artigo em Inglês | MEDLINE | ID: mdl-31965982

RESUMO

Epigenetic mechanisms including the post-translational modifications of histones, incorporation of histone variants and DNA methylation have been suggested to play an important role in genome plasticity by allowing the cellular environment to define gene expression and the phenotype of an organism. Studies over the past decade have elucidated how these epigenetic mechanisms are significant in orchestrating various biological processes and contribute to different pathophysiological states. However, the role of histone isoforms and their impact on different phenotypes and physiological processes associated with diseases are not fully clear. This review is focussed on the recent advances in our understanding of the complexity of eukaryotic H2A isoforms and their roles in defining nucleosome organization. We elaborate on their potential roles in genomic complexity and regulation of gene expression, and thereby on their overall contribution towards cellular phenotype and development of diseases.


Assuntos
Epigênese Genética/genética , Epigenoma/genética , Histonas/genética , Regulação da Expressão Gênica/genética , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Humanos , Nucleossomos/genética , Isoformas de Proteínas/genética , Processamento de Proteína Pós-Traducional/genética
12.
J Pathol ; 250(1): 9-18, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31579936

RESUMO

Molecular chaperones, many of which are heat shock proteins (Hsps), are components of the chaperoning system and when defective can cause disease, the chaperonopathies. Chaperone-gene variants cause genetic chaperonopathies, whereas in the acquired chaperonopathies the genes are normal, but their protein products are not, due to aberrant post-transcriptional mechanisms, e.g. post-translational modifications (PTMs). Since the chaperoning system is widespread in the body, chaperonopathies affect various tissues and organs, making these diseases of interest to a wide range of medical specialties. Genetic chaperonopathies are uncommon but the acquired ones are frequent, encompassing various types of cancer, and inflammatory and autoimmune disorders. The clinical picture of chaperonopathies is known. Much less is known on the impact that pathogenic mutations and PTMs have on the properties and functions of chaperone molecules. Elucidation of these molecular alterations is necessary for understanding the mechanisms underpinning the tissue and organ abnormalities occurring in patients. To illustrate this issue, we discuss structural-functional alterations caused by mutation in the chaperones CCT5 and HSPA9, and PTM effects on Hsp60. The data provide insights into what may happen when CCT5 and HSPA9 malfunction in patients, e.g. accumulation of cytotoxic protein aggregates with tissue destruction; or for Hsp60 with aberrant PTM, degradation and/or secretion of the chaperonin with mitochondrial damage. These and other possibilities are now open for investigation. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Doenças Genéticas Inatas/genética , Chaperonas Moleculares/genética , Mutação , Animais , Chaperonina 60/genética , Chaperonina 60/metabolismo , Chaperonina com TCP-1/genética , Chaperonina com TCP-1/metabolismo , Regulação da Expressão Gênica , Doenças Genéticas Inatas/metabolismo , Doenças Genéticas Inatas/patologia , Doenças Genéticas Inatas/terapia , Predisposição Genética para Doença , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Chaperonas Moleculares/metabolismo , Fenótipo , Prognóstico , Processamento de Proteína Pós-Traducional , Fatores de Risco , Transdução de Sinais
13.
Ann N Y Acad Sci ; 1466(1): 93-103, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31647584

RESUMO

Assessment of telomere length (TL) in peripheral blood leukocytes is part of the diagnostic algorithm applied to patients with acquired bone marrow failure syndromes (BMFSs) and dyskeratosis congenita (DKC). Monochrome multiplex-quantitative polymerase chain reaction (MM-qPCR) and fluorescence in situ hybridization (flow-FISH) are methodologies available for TL screening. Dependent on TL expressed in relation to percentiles of healthy controls, further genetic testing for inherited mutations in telomere maintenance genes is recommended. However, the correct threshold to trigger this genetic workup is still under debate. Here, we prospectively compared MM-qPCR and flow-FISH regarding their capacity for accurate identification of DKC patients. All patients (n = 105) underwent genetic testing by next-generation sequencing and in 16 patients, mutations in DKC-relevant genes were identified. Whole leukocyte TL of patients measured by MM-qPCR was found to be moderately correlated with lymphocyte TL measured by flow-FISH (r² = 0.34; P < 0.0001). The sensitivity of both methods was high, but the specificity of MM-qPCR (29%) was significantly lower compared with flow-FISH (58%). These results suggest that MM-qPCR of peripheral blood cells is inferior to flow-FISH for clinical routine screening for suspected DKC in adult patients with BMFS due to lower specificity and a higher rate of false-positive results.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Hibridização in Situ Fluorescente/métodos , Reação em Cadeia da Polimerase Multiplex/métodos , Homeostase do Telômero/fisiologia , Telômero/genética , Adulto , Idoso , Transtornos da Insuficiência da Medula Óssea/diagnóstico , Transtornos da Insuficiência da Medula Óssea/genética , Transtornos da Insuficiência da Medula Óssea/patologia , Estudos de Casos e Controles , Estudos de Coortes , Disceratose Congênita/diagnóstico , Disceratose Congênita/genética , Disceratose Congênita/patologia , Feminino , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real/métodos , Encurtamento do Telômero/genética , Adulto Jovem
14.
Am J Clin Pathol ; 153(1): 119-125, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31584623

RESUMO

OBJECTIVES: We studied clinicopathologic features of congenital hepatic fibrosis (CHF) that could aid the diagnosis of this relatively rare condition during adulthood. METHODS: Five consecutive adult CHF cases were identified in a single institution. RESULTS: Clinical manifestations of CHF varied from asymptomatic to requiring liver transplantation. Three of five cases had other disease associations, including Joubert syndrome, Caroli disease, polycystic kidney disease, and congenital anomaly of hepatic vasculature. No unique common radiologic findings were found. Histologically, all cases showed characteristic abnormal interlobular bile ducts embedded in fibrotic portal stroma, with varying degrees of liver fibrosis. CONCLUSIONS: While other disease associations and characteristic liver histomorphology are helpful clues to suspect the diagnosis of CHF in adult patients, other differential diagnoses should be excluded clinically and radiologically. This study highlights the importance of a multidisciplinary diagnostic approach by pathologists, radiologists, and hepatologists for the accurate diagnosis of CHF during adulthood.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Cirrose Hepática/diagnóstico , Transplante de Fígado , Adulto , Idoso , Feminino , Doenças Genéticas Inatas/patologia , Humanos , Fígado/patologia , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade
15.
Nat Genet ; 52(1): 35-39, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31873297

RESUMO

With large-scale population sequencing projects gathering pace, there is a need for strategies that advance disease gene prioritization1,2. Metrics that provide information about a gene and its ability to tolerate protein-altering variation can aid in clinical interpretation of human genomes and can advance disease gene discovery1-4. Previous reported methods analyzed the total variant load in a gene1-4, but did not analyze the distribution pattern of variants within a gene. Using data from 138,632 exome and genome sequences2, we developed gene variation intolerance rank (GeVIR), a continuous gene-level metric for 19,361 genes that is able to prioritize both dominant and recessive Mendelian disease genes5, that outperforms missense constraint metrics3 and that is comparable-but complementary-to loss-of-function (LOF) constraint metrics2. GeVIR is also able to prioritize short genes, for which LOF constraint cannot be estimated with confidence2. The majority of the most intolerant genes identified here have no defined phenotype and are candidates for severe dominant disorders.


Assuntos
Biologia Computacional/métodos , Doenças Genéticas Inatas/patologia , Marcadores Genéticos , Variação Genética , Genoma Humano , Mutação , Proteínas/genética , Doenças Genéticas Inatas/genética , Humanos , Fenótipo
16.
J Cereb Blood Flow Metab ; 40(3): 622-638, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-30819023

RESUMO

Compromised Na+/K+-ATPase function is associated with the occurrence of spreading depolarization (SD). Mutations in ATP1A2, the gene encoding the α2 isoform of the Na+/K+-ATPase, were identified in patients with familial hemiplegic migraine type 2 (FHM2), a Mendelian model disease for SD. This suggests a distinct role for the α2 isoform in modulating SD susceptibility and raises questions about underlying mechanisms including the roles of other Na+/K+-ATPase α isoforms. Here, we investigated the effects of genetic ablation and pharmacological inhibition of α1, α2, and α3 on SD using heterozygous knock-out mice. We found that only α2 heterozygous mice displayed higher SD susceptibility when challenged with prolonged extracellular high potassium concentration ([K+]o), a pronounced post SD oligemia and higher SD speed in-vivo. By contrast, under physiological [K+]o, α2 heterozygous mice showed similar SD susceptibility compared to wild-type littermates. Deficiency of α3 resulted in increased resistance against electrically induced SD in-vivo, whereas α1 deficiency did not affect SD. The results support important roles of the α2 isoform in SD. Moreover, they suggest that specific experimental conditions can be necessary to reveal an inherent SD phenotype by driving a (meta-) stable system into decompensation, reminiscent of the episodic nature of SDs in various diseases.


Assuntos
Depressão Alastrante da Atividade Elétrica Cortical , Doenças Genéticas Inatas/enzimologia , Doenças Genéticas Inatas/genética , Enxaqueca com Aura/enzimologia , Enxaqueca com Aura/genética , ATPase Trocadora de Sódio-Potássio/deficiência , Animais , Modelos Animais de Doenças , Doenças Genéticas Inatas/patologia , Isoenzimas/genética , Isoenzimas/metabolismo , Camundongos , Camundongos Knockout , Mutação , ATPase Trocadora de Sódio-Potássio/metabolismo
17.
Hematology Am Soc Hematol Educ Program ; 2019(1): 391-396, 2019 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-31808840

RESUMO

In the patient presenting with an elevated blood count who does not have an acquired clonal disorder causing a myeloproliferative neoplasm, hereditary erythrocytosis or hereditary thrombocytosis needs to be considered as a possible explanation. A young patient and/or those with a family history of myeloproliferative neoplasm should specifically raise this possibility. Among the causes of hereditary erythrocytosis are mutations in the genes in the oxygen sensing pathway and high-affinity hemoglobins. Hereditary thrombocytosis has been shown to be accounted for by mutations in THPO, MPL, and JAK2 genes. In those who have a possible hereditary erythrocytosis or thrombocytosis, the investigative pathway includes specific investigation to rule out the more common acquired clonal disorders, and, if indicated, other secondary causes, measurement of specific cytokines as indicated, and search for specific identified molecular lesions that have been shown to cause these hereditary disorders. There remain individuals who appear to have a hereditary disorder in whom a genetic lesion cannot currently be identified.


Assuntos
Doenças Genéticas Inatas , Janus Quinase 2/genética , Mutação , Policitemia , Receptores de Trombopoetina/genética , Trombocitose , Adulto , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Humanos , Masculino , Policitemia/diagnóstico , Policitemia/genética , Policitemia/patologia , Trombocitose/diagnóstico , Trombocitose/genética , Trombocitose/patologia
18.
Int J Mol Sci ; 20(23)2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31801211

RESUMO

The gene editing tool CRISPR-Cas has become the foundation for developing numerous molecular systems used in research and, increasingly, in medical practice. In particular, Cas proteins devoid of nucleolytic activity (dead Cas proteins; dCas) can be used to deliver functional cargo to programmed sites in the genome. In this review, we describe current CRISPR systems used for developing different dCas-based molecular approaches and summarize their most significant applications. We conclude with comments on the state-of-art in the CRISPR field and future directions.


Assuntos
Proteína 9 Associada à CRISPR/genética , Sistemas CRISPR-Cas , Doenças Transmissíveis/terapia , Edição de Genes/métodos , Doenças Genéticas Inatas/terapia , Inflamação/terapia , Neoplasias/terapia , Proteína 9 Associada à CRISPR/metabolismo , Cromatina/química , Cromatina/metabolismo , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Doenças Transmissíveis/genética , Doenças Transmissíveis/metabolismo , Doenças Transmissíveis/patologia , Metilação de DNA , Epigênese Genética , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/metabolismo , Doenças Genéticas Inatas/patologia , Genoma Humano , Histonas/genética , Histonas/metabolismo , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , RNA Guia/genética , RNA Guia/metabolismo
19.
Mutat Res ; 848: 403023, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31708072

RESUMO

As part of the 7th International Workshops on Genotoxicity Testing held in Tokyo, Japan in November 2017, a workgroup of experts reviewed and assessed the risk of aneugens for human health. The present manuscript is one of three manuscripts from the workgroup and reports on the unanimous consensus reached on the evidence for aneugens affecting germ cells, their mechanisms of action and role in hereditary diseases. There are 24 chemicals with strong or sufficient evidence for germ cell aneugenicity providing robust support for the ability of chemicals to induce germ cell aneuploidy. Interference with microtubule dynamics or inhibition of topoisomerase II function are clear characteristics of germ cell aneugens. Although there are mechanisms of chromosome segregation that are unique to germ cells, there is currently no evidence for germ cell-specific aneugens. However, the available data are heavily skewed toward chemicals that are aneugenic in somatic cells. Development of high-throughput screening assays in suitable animal models for exploring additional targets for aneuploidy induction, such as meiosis-specific proteins, and to prioritize chemicals for the potential to be germ cell aneugens is encouraged. Evidence in animal models support that: oocytes are more sensitive than spermatocytes and somatic cells to aneugens; exposure to aneugens leads to aneuploid conceptuses; and, the frequencies of aneuploidy are similar in germ cells and zygotes. Although aneuploidy in germ cells is a significant cause of infertility and pregnancy loss in humans, there is currently limited evidence that aneugens induce hereditary diseases in human populations because the great majority of aneuploid conceptuses die in utero. Overall, the present work underscores the importance of protecting the human population from exposure to chemicals that can induce aneuploidy in germ cells that, in contrast to carcinogenicity, is directly linked to an adverse outcome.


Assuntos
Aneugênicos/toxicidade , Aneuploidia , Carcinogênese , Doenças Genéticas Inatas/patologia , Células Germinativas/efeitos dos fármacos , Animais , Células Germinativas/patologia , Humanos , Fatores de Risco
20.
Sci Rep ; 9(1): 14036, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31575891

RESUMO

TRAPPC11 was identified as a component of the TRAPP III complex that functions in membrane trafficking and autophagy. Variants in TRAPPC11 have been reported to be associated with a broad spectrum of phenotypes but all affected individuals display muscular pathology. Identifying additional variants will further our understanding of the clinical spectrum of phenotypes and will reveal regions of the protein critical for its functions. Here we report three individuals from unrelated families that have bi-allellic TRAPPC11 variants. Subject 1 harbors a compound heterozygous variant (c.1287 + 5G > A and c.3379_3380insT). The former variant results in a partial deletion of the foie gras domain (p.Ala372_Ser429del), while the latter variant results in a frame-shift and extension at the carboxy terminus (p.Asp1127Valfs*47). Subjects 2 and 3 both harbour a homozygous missense variant (c.2938G > A; p.Gly980Arg). Fibroblasts from all three subjects displayed membrane trafficking defects manifested as delayed endoplasmic reticulum (ER)-to-Golgi transport and/or a delay in protein exit from the Golgi. All three individuals also show a defect in glycosylation of an ER-resident glycoprotein. However, only the compound heterozygous subject displayed an autophagic flux defect. Collectively, our characterization of these individuals with bi-allelic TRAPPC11 variants highlights the functional importance of the carboxy-terminal portion of the protein.


Assuntos
Proteínas de Transporte Vesicular/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Pré-Escolar , Feminino , Frequência do Gene , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Variação Genética/genética , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Hipotonia Muscular/genética , Músculo Esquelético/patologia , Proteínas de Transporte Vesicular/química , Proteínas de Transporte Vesicular/genética
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