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BACKGROUND: De novo mutations (DNMs) are variants that occur anew in the offspring of noncarrier parents. They are not inherited from either parent but rather result from endogenous mutational processes involving errors of DNA repair/replication. These spontaneous errors play a significant role in the causation of genetic disorders, and their importance in the context of molecular diagnostic medicine has become steadily more apparent as more DNMs have been reported in the literature. In this study, we examined 46,489 disease-associated DNMs annotated by the Human Gene Mutation Database (HGMD) to ascertain their distribution across gene and disease categories. RESULTS: Most disease-associated DNMs reported to date are found to be associated with developmental and psychiatric disorders, a reflection of the focus of sequencing efforts over the last decade. Of the 13,277 human genes in which DNMs have so far been found, the top-10 genes with the highest proportions of DNM relative to gene size were H3-3 A, DDX3X, CSNK2B, PURA, ZC4H2, STXBP1, SCN1A, SATB2, H3-3B and TUBA1A. The distribution of CADD and REVEL scores for both disease-associated DNMs and those mutations not reported to be de novo revealed a trend towards higher deleteriousness for DNMs, consistent with the likely lower selection pressure impacting them. This contrasts with the non-DNMs, which are presumed to have been subject to continuous negative selection over multiple generations. CONCLUSION: This meta-analysis provides important information on the occurrence and distribution of disease-associated DNMs in association with heritable disease and should make a significant contribution to our understanding of this major type of mutation.
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Células Germinativas , Pais , Humanos , MutaçãoRESUMO
With the advent of next-generation sequencing, an increasing number of cases of de novo variants in domestic animals have been reported in scientific literature primarily associated with clinically severe phenotypes. The emergence of new variants at each generation is a crucial aspect in understanding the pathology of early-onset diseases in animals and can provide valuable insights into similar diseases in humans. With the aim of collecting deleterious de novo variants in domestic animals, we searched the scientific literature and compiled reports on 42 de novo variants in 31 genes in domestic animals. No clear disease-associated phenotype has been established in humans for three of these genes (NUMB, ANKRD28 and KCNG1). For the remaining 28 genes, a strong similarity between animal and human phenotypes was recognized from available information in OMIM and OMIA, revealing the importance of comparative studies and supporting the use of domestic animals as natural models for human diseases, in line with the One Health approach.
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Animais Domésticos , Animais , Animais Domésticos/genética , Fenótipo , Doenças Genéticas Inatas/veterinária , Doenças Genéticas Inatas/genética , Variação GenéticaRESUMO
INTRODUCTION: Audiovestibular dysfunction has been reported in many autoimmune connective tissue diseases, including systemic sclerosis (SSc). OBJECTIVE: To assess the prevalence and features of audiological and vestibular disturbances in SSc patients and evaluate their relationship with disease duration, clinical features, nailfold videocapillaroscopy pattern, and immunologic profiles. METHOD: A matched case-control study was conducted in a rheumatology clinic of a second-level hospital over 24 months. All patients underwent a detailed ear, nose, and throat examination, as well as audiometric and vestibular assessments, including pure tone audiometry, speech audiometry, immittance tests, and the Video Head Impulse Test. RESULTS: Thirty-five SSc patients and 24 healthy controls were included in the study. In the SSc group, subjective hearing loss was reported by 17.1% of patients, vertigo by 14.3%, tinnitus by 11.4%, and dizziness by 5.7%. Sensorineural hearing loss was identified in 42.9% of SSc patients, significantly higher than in the control group (p = 0.013). There was no correlation between audiological manifestations and clinical symptoms, organ involvement, immunologic characteristics, and treatment. Vestibular dysfunction was detected in 60% of SSc patients, significantly higher than the control group (p = 0.05). A significant correlation was found between abnormal Video Head Impulse Test and the presence of anti-RNA polymerase III and anti-Th/To antibodies (p = 0.05 and p = 0.034, respectively). CONCLUSION: Our study revealed an increased prevalence of sensorineural hearing loss and vestibulopathy in SSc patients.
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Understanding the role of common polymorphisms in modulating the clinical phenotype when they co-occur with a disease-causing lesion is of critical importance in medical genetics. We explored the impact of apparently neutral common polymorphisms, using the gene encoding the urea cycle enzyme, ornithine transcarbamylase (OTC), as a model system. Distinct combinations of genetic backgrounds embracing two missense polymorphisms were created in cis with the pathogenic p.Arg40His replacement. In vitro enzymatic assays revealed that the polymorphic variants were able to modulate OTC activity both in the presence or absence of the pathogenic lesion. First, we found that the combination of the minor alleles of polymorphisms p.Lys46Arg and p.Gln270Arg significantly enhanced enzymatic activity in the wild-type protein. Second, enzymatic assays revealed that the minor allele of the p.Gln270Arg polymorphism was capable of ameliorating OTC activity when combined in cis with the pathogenic p.Arg40His replacement. Structural analysis predicted that the minor allele of the p.Gln270Arg polymorphism would serve to stabilize the OTC wild-type protein, thereby corroborating the results of the experimental assays. Our findings demonstrate the potential importance of cis-interactions between common polymorphic variants and pathogenic missense mutations and illustrate how standing genetic variation can modulate protein function.
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Doença da Deficiência de Ornitina Carbomoiltransferase , Ornitina Carbamoiltransferase , Alelos , Humanos , Mutação de Sentido Incorreto , Ornitina Carbamoiltransferase/genética , Doença da Deficiência de Ornitina Carbomoiltransferase/genética , Polimorfismo GenéticoRESUMO
A non-negligible proportion of human pathogenic variants are known to be present as wild type in at least some non-human mammalian species. The standard explanation for this finding is that molecular mechanisms of compensatory epistasis can alleviate the mutations' otherwise pathogenic effects. Examples of compensated variants have been described in the literature but the interacting residue(s) postulated to play a compensatory role have rarely been ascertained. In this study, the examination of five human X-chromosomally encoded proteins (FIX, GLA, HPRT1, NDP and OTC) allowed us to identify several candidate compensated variants. Strong evidence for a compensated/compensatory pair of amino acids in the coagulation FIXa protein (involving residues 270 and 271) was found in a variety of mammalian species. Both amino acid residues are located within the 60-loop, spatially close to the 39-loop that performs a key role in coagulation serine proteases. To understand the nature of the underlying interactions, molecular dynamics simulations were performed. The predicted conformational change in the 39-loop consequent to the Glu270Lys substitution (associated with hemophilia B) appears to impair the protein's interaction with its substrate but, importantly, such steric hindrance is largely mitigated in those proteins that carry the compensatory residue (Pro271) at the neighboring amino acid position.
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Cromossomos Humanos X/genética , Epistasia Genética , Fator IXa , Simulação de Dinâmica Molecular , Mutação de Sentido Incorreto , Substituição de Aminoácidos , Fator IXa/química , Fator IXa/genética , HumanosRESUMO
OBJECTIVE: To describe the clinical, biochemical, and genetic features of both new and previously reported patients with congenital disorders of glycosylation (CDGs) diagnosed in Portugal over the last 20 years. STUDY DESIGN: The cohort includes patients with an unexplained multisystem or single organ involvement, with or without psychomotor disability. Serum sialotransferrin isoforms and, whenever necessary, apolipoprotein CIII isoforms and glycan structures were analyzed. Additional studies included measurement of phosphomannomutase (PMM) activity and analysis of lipid-linked oligosaccharides in fibroblasts. Sanger sequencing and massive parallel sequencing were used to identify causal variants or the affected gene, respectively. RESULTS: Sixty-three individuals were diagnosed covering 14 distinct CDGs; 43 patients diagnosed postnatally revealed a type 1, 14 a type 2, and 2 a normal pattern on serum transferrin isoelectrofocusing. The latter patients were identified by whole exome sequencing. Nine of them presented also a hypoglycosylation pattern on apolipoprotein CIII isoelectrofocusing, pointing to an associated O-glycosylation defect. Most of the patients (62%) are PMM2-CDG and the remaining carry pathogenic variants in ALG1, ATP6AP1, ATP6AP2, ATP6V0A2, CCDC115, COG1, COG4, DPAGT1, MAN1B1, SLC35A2, SRD5A3, RFT1, or PGM1. CONCLUSIONS: Portuguese patients with CDGs are presented in this report, some of them showing unique clinical phenotypes. Among the 14 genes mutated in Portuguese individuals, 8 are shared with a previously reported Spanish cohort. However, regarding the mutational spectrum of PMM2-CDG, the most frequent CDG, a striking similarity between the 2 populations was found, as only 1 mutated allele found in the Portuguese group has not been reported in Spain.
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Defeitos Congênitos da Glicosilação/diagnóstico , Defeitos Congênitos da Glicosilação/genética , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Portugal , Fatores de Tempo , Adulto JovemRESUMO
The Human Gene Mutation Database (HGMD®) constitutes a comprehensive collection of published germline mutations in nuclear genes that are thought to underlie, or are closely associated with human inherited disease. At the time of writing (June 2020), the database contains in excess of 289,000 different gene lesions identified in over 11,100 genes manually curated from 72,987 articles published in over 3100 peer-reviewed journals. There are primarily two main groups of users who utilise HGMD on a regular basis; research scientists and clinical diagnosticians. This review aims to highlight how to make the most out of HGMD data in each setting.
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Bases de Dados Genéticas , Genoma Humano , Mutação em Linhagem Germinativa , Polimorfismo Genético , Bibliometria , Pesquisa Biomédica/métodos , Predisposição Genética para Doença , Humanos , Parcerias Público-PrivadasRESUMO
Neurodevelopmental disorders (NDDs) represent a growing medical challenge in modern societies. Ever-increasing sophisticated diagnostic tools have been continuously revealing a remarkably complex architecture that embraces genetic mutations of distinct types (chromosomal rearrangements, copy number variants, small indels, and nucleotide substitutions) with distinct frequencies in the population (common, rare, de novo). Such a network of interacting players creates difficulties in establishing rigorous genotype-phenotype correlations. Furthermore, individual lifestyles may also contribute to the severity of the symptoms fueling a large spectrum of gene-environment interactions that have a key role on the relationships between genotypes and phenotypes.Herein, a review of the genetic discoveries related to NDDs is presented with the aim to provide useful general information for the medical community.
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Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença , Transtornos do Neurodesenvolvimento/genética , Interação Gene-Ambiente , Estudos de Associação Genética , Genótipo , Humanos , Mutação/genética , Transtornos do Neurodesenvolvimento/patologiaRESUMO
Copy number variants (CNVs) are important contributors to the human pathogenic genetic diversity as demonstrated by a number of cases reported in the literature. The high homology between repetitive elements may guide genomic stability which will give rise to CNVs either by non-allelic homologous recombination (NAHR) or non-homologous end joining (NHEJ). Here, we present a short guide based on previously documented cases of disease-associated CNVs in order to provide a general view on the impact of repeated elements on the stability of the genomic sequence and consequently in the origin of the human pathogenic variome.
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Known examples of ancient identical-by-descent genetic variants being shared between evolutionarily related species, known as trans-species polymorphisms (TSPs), result from counterbalancing selective forces acting on target genes to confer resistance against infectious agents. To date, putative TSPs between humans and other primate species have been identified for the highly polymorphic major histocompatibility complex (MHC), the histo-blood ABO group, two antiviral genes (ZC3HAV1 and TRIM5), an autoimmunity-related gene LAD1 and several non-coding genomic segments with a putative regulatory role. Although the number of well-characterized TSPs under long-term balancing selection is still very small, these examples are connected by a common thread, namely that they involve genes with key roles in the immune system and, in heterozygosity, appear to confer genetic resistance to pathogens. Here, we review known cases of shared polymorphism that appear to be under long-term balancing selection in humans and the great apes. Although the specific selective agent(s) responsible are still unknown, these TSPs may nevertheless be seen as constituting important adaptive events that have occurred during the evolution of the primate immune system.
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Evolução Molecular , Imunidade Inata/genética , Polimorfismo Genético , Seleção Genética , Sistema ABO de Grupos Sanguíneos/genética , Animais , Fatores de Restrição Antivirais , Autoantígenos/genética , Proteínas de Transporte/genética , Hominidae/genética , Humanos , Complexo Principal de Histocompatibilidade/genética , Colágenos não Fibrilares/genética , Proteínas de Ligação a RNA/genética , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases , Colágeno Tipo XVIIRESUMO
Perennial plants create productive and biodiverse hotspots, known as fertile islands, beneath their canopies. These hotspots largely determine the structure and functioning of drylands worldwide. Despite their ubiquity, the factors controlling fertile islands under conditions of contrasting grazing by livestock, the most prevalent land use in drylands, remain virtually unknown. Here we evaluated the relative importance of grazing pressure and herbivore type, climate and plant functional traits on 24 soil physical and chemical attributes that represent proxies of key ecosystem services related to decomposition, soil fertility, and soil and water conservation. To do this, we conducted a standardized global survey of 288 plots at 88 sites in 25 countries worldwide. We show that aridity and plant traits are the major factors associated with the magnitude of plant effects on fertile islands in grazed drylands worldwide. Grazing pressure had little influence on the capacity of plants to support fertile islands. Taller and wider shrubs and grasses supported stronger island effects. Stable and functional soils tended to be linked to species-rich sites with taller plants. Together, our findings dispel the notion that grazing pressure or herbivore type are linked to the formation or intensification of fertile islands in drylands. Rather, our study suggests that changes in aridity, and processes that alter island identity and therefore plant traits, will have marked effects on how perennial plants support and maintain the functioning of drylands in a more arid and grazed world.
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Herbivoria , Solo , Solo/química , Plantas , Ecossistema , Clima Desértico , AnimaisRESUMO
NET family members have recently emerged as important players in the development of multiple structures, from the trachea of fly larvae to the vertebrate eye and human breast cancers. However, their mechanisms of action are still poorly understood, and we lack a detailed characterization of their functional domains, as well as gene expression patterns-particularly in adult mammals. Here, we present a characterization of human NLZ1/ZNF703 (NocA-like zinc finger 1/Zinc finger 703), one of the two human NET family member genes. We show that the gene is ubiquitously expressed in adult human and mouse tissues, that three mRNA species with the same coding sequence are generated by alternative polyadenylation, and that the encoded protein contains six evolutionarily conserved domains, three of which are specific to NET proteins. Finally, we present functional evidence that these domains are necessary for proper subcellular distribution of and transcription repression by the NLZ1 protein, but not for its interaction with Groucho family co-repressors.
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Proteínas de Transporte/genética , Proteínas de Ligação a DNA/genética , Poliadenilação , RNA Mensageiro/genética , Proteínas Repressoras/genética , Adulto , Sequência de Aminoácidos , Animais , Sequência de Bases , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Núcleo Celular/metabolismo , Sequência Conservada , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Células HEK293 , Células HeLa , Humanos , Camundongos , Dados de Sequência Molecular , Estrutura Terciária de Proteína , Transporte Proteico , RNA Mensageiro/química , RNA Mensageiro/metabolismo , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Homologia de Sequência de Aminoácidos , Transdução de Sinais , Transcrição GênicaRESUMO
Complex III of the mitochondrial respiratory chain (CIII) catalyzes transfer of electrons from reduced coenzyme Q to cytochrome c. Low biochemical activity of CIII is not a frequent etiology in disorders of oxidative metabolism and is genetically heterogeneous. Recently, mutations in the human tetratricopeptide 19 gene (TTC19) have been involved in the etiology of CIII deficiency through impaired assembly of the holocomplex. We investigated a consanguineous Portuguese family where four siblings had reduced enzymatic activity of CIII in muscle and harbored a novel homozygous mutation in TTC19. The clinical phenotype in the four sibs was consistent with severe olivo-ponto-cerebellar atrophy, although their age at onset differed slightly. Interestingly, three patients also presented progressive psychosis. The mutation resulted in almost complete absence of TTC19 protein, defective assembly of CIII in muscle, and enhanced production of reactive oxygen species in cultured skin fibroblasts. Our findings add to the array of mutations in TTC19, corroborate the notion of genotype/phenotype variability in mitochondrial encephalomyopathies even within a single family, and indicate that psychiatric manifestations are a further presentation of low CIII.
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Predisposição Genética para Doença/genética , Proteínas de Membrana/genética , Mitocôndrias/genética , Encefalomiopatias Mitocondriais/genética , Proteínas Mitocondriais/genética , Mutação/genética , Células Cultivadas , Feminino , Fibroblastos/metabolismo , Heterogeneidade Genética , Testes Genéticos/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Mitocondriais/metabolismo , Linhagem , FenótipoRESUMO
The increasing use of plant evidence in forensic investigations gave rise to a powerful new discipline - Forensic Botany - that analyses micro- or macroscopic plant materials, such as the totality or fragments of an organ (i.e., leaves, stems, seeds, fruits, roots) and tissue (i.e., pollen grains, spores, fibers, cork) or its chemical composition (i. e., secondary metabolites, isotopes, DNA, starch grains). Forensic botanists frequently use microscopy, chemical analysis, and botanical expertise to identify and interpret evidence crucial to solving civil and criminal issues, collaborating in enforcing laws or regulations, and ensuring public health safeguards. The present work comprehensively examines the current state and future potential of Forensic Botany. The first section conveys the critical steps of plant evidence collection, documentation, and preservation, emphasizing the importance of these initial steps in maintaining the integrity of the items. It explores the different molecular analyses, covering the identification of plant species and varieties or cultivars, and discusses the limitations and challenges of these techniques in forensics. The subsequent section covers the diversity of Forensic Botany approaches, examining how plant evidence exposes food and pharmaceutical frauds, uncovers insufficient or erroneous labeling, traces illegal drug trafficking routes, and combats the illegal collection or trade of protected species and derivatives. National and global security issues, including the implications of biological warfare, bioterrorism, and biocrime are addressed, and a review of the contributions of plant evidence in crime scene investigations is provided, synthesizing a comprehensive overview of the diverse facets of Forensic Botany.
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Botânica , Plantas , Plantas/genética , Medicina Legal/métodos , Pólen , SementesRESUMO
Gene duplication plays a significant role in evolution. Paralogous gene copies may be lost due to the successive accumulation of deleterious mutations or remain active in the genome. In this work, a partial duplication of an X-linked region in the Macaca genus is identified and explored. Genomic comparisons reveal that the duplication encompasses the genes encoding ornithine transcarbamylase (OTC) and retinitis pigmentosa GTPase regulator (RPGR), spanning over 0.1 Mb on the chromosome 9 of Macaca. According to our analyses, the duplicated region of chromosome 9 involves partial coding sequences of both OTC and RPGR genes. Analyses of the selective pressures did not reveal significant differences in the ratio between nonsynonymous and synonymous mutations (w<1), suggesting that no selective pressures were acting in the evolutionary process. Reports for a biological role regarding some partial duplications exist in the literature, therefore, although being rare events, partial duplications of functionally important genes are worthy of study so that their impact can be explored.
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Genes Ligados ao Cromossomo X , Macaca , Animais , Macaca/genética , Duplicação Gênica , Primatas/genética , Éxons , Proteínas do Olho/genéticaRESUMO
Paraneoplastic syndromes are rare and diverse conditions caused by either an abnormal chemical signaling molecule produced by tumor cells or a body's immune response against the tumor itself. These syndromes can manifest in a variable, multisystemic and often nonspecific manner posing a diagnostic challenge. We report the case of an 81-year-old woman who exhibited severe hypokalemia, metabolic alkalosis, and worsening hyperglycemia. The investigation was consistent with adrenocorticotropin (ACTH)-dependent Cushing's syndrome and, eventually, the patient was diagnosed with stage IV primary small-cell lung cancer (SCLC). SCLC is known to be associated with paraneoplastic syndromes, including Cushing's syndrome caused by ectopic adrenocorticotropin (ACTH) secretion. Despite being associated with very poor outcomes, managing these syndromes can be challenging and may hold prognostic significance.
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Patients with psoriasis can have higher rates of hypertension, diabetes mellitus 2, and dyslipidemia. This study aimed to assess the association between psoriasis, myocardial infarction (MI), and stroke. A systematic review was carried out using PubMed/Medline, EMBASE, and LILACS databases searching for observational studies that assessed stroke and/or MI in patients diagnosed with psoriasis vulgaris compared to non-psoriatic patients. A total of 649 articles were identified but only 15 were included in the study. Although there were studies that have observed a significant positive association between psoriasis and MI or stroke, an almost equal number of studies showed no statistically significant association. The relationship between psoriasis and ischemic cardiovascular events is still controversial and it is difficult to establish psoriasis as the etiology of these events.
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Hipertensão , Infarto do Miocárdio , Psoríase , Acidente Vascular Cerebral , Humanos , Psoríase/complicações , Psoríase/epidemiologia , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/etiologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/complicações , Fatores de Risco , Hipertensão/complicaçõesRESUMO
Oral transmission from the consumption of processed food with triatomines and/or their feces infected with Trypanosoma cruzi prevails among recent cases of Chagas disease in Brazil. In Paraíba, a state of the Brazilian northeast, there was an outbreak caused by the consumption of sugarcane juice that resulted in 26 cases of infection and one death. Until now, 10 species of triatomines have been reported in this Brazilian state. Thus, we developed a dichotomous key to assist in the correct identification of Paraíba triatomines based on cytogenetic data. The dichotomous key allowed the differentiation of all the species in this state. Although the purpose of CytoKeys is not to replace dichotomous keys based on morphological data, the use of these complementary keys can help to solve taxonomic problems, preventing identification errors, especially between similar species such as Triatoma brasiliensis and Triatoma petrocchiae, both present in the Brazilian northeast.
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Doença de Chagas , Triatoma , Triatominae , Trypanosoma cruzi , Humanos , Animais , Brasil/epidemiologia , Insetos Vetores , Doença de Chagas/epidemiologia , Triatoma/genética , Trypanosoma cruzi/genética , Surtos de Doenças , Análise CitogenéticaRESUMO
Chagas disease affects about eight million people. In view of the issues related to the influence of anthropogenic changes in the dynamics of the distribution and reproductive interaction of triatomines, we performed experimental crosses between species of the Rhodniini tribe in order to evaluate interspecific reproductive interactions and hybrid production capacity. Reciprocal crossing experiments were conducted among Rhodnius brethesi × R. pictipes, R. colombiensis × R. ecuadoriensis, R. neivai × R. prolixus, R. robustus × R. prolixus, R. montenegrensis × R. marabaensis; R. montenegrensis × R. robustus, R. prolixus × R. nasutus and R. neglectus × R. milesi. With the exception of crosses between R. pictipes â × R. brethesi â, R. ecuadoriensis â × R. colombiensis â and R. prolixus â × R. neivai â, all experimental crosses resulted in hybrids. Our results demonstrate that both allopatric and sympatric species produce hybrids, which can generate concern for public health agencies in the face of current anthropogenic events. Thus, we demonstrate that species of the Rhodniini tribe are capable of producing hybrids under laboratory conditions. These results are of great epidemiological importance and raise an important discussion about the influence of climatic and environmental interactions on Chagas disease dynamics.