Two-step ATP-driven opening of cohesin head.

The cohesin ring is a protein complex composed of four core subunits: Smc1A, Smc3, Rad21 and Stag1/2. It is involved in chromosome segregation, DNA repair, chromatin organization and transcription regulation. Opening of the ring occurs at the “head” structure, formed of the ATPase domains of Smc1A and Smc3 and Rad21. We investigate the mechanisms of the cohesin ring opening using techniques of free molecular dynamics (MD), steered MD and quantum mechanics/molecular mechanics MD (QM/MM MD). The study allows the thorough analysis of the opening events at the atomic scale: i) ATP hydrolysis at the Smc1A site, evaluating the role of the carboxy-terminal domain of Rad21 in the process; ii) the activation of the Smc3 site potentially mediated by the movement of specific amino acids; and iii) opening of the head domains after the two ATP hydrolysis events. Our study suggests that the cohesin ring opening is triggered by a sequential activation of the ATP sites in which ATP hydrolysis at the Smc1A site induces ATPase activity at the Smc3 site. Our analysis also provides an explanation for the effect of pathogenic variants related to cohesinopathies and cancer.post-print4709 K

Things are not always what they seem: From Cornelia de Lange to KBG phenotype in a girl with genetic variants in NIPBL and ANKRD11.

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Molecular Basis of the Schuurs–Hoeijmakers Syndrome: What We Know about the Gene and the PACS-1 Protein and Novel Therapeutic Approaches

The Schuurs–Hoeijmakers syndrome (SHMS) or PACS1 Neurodevelopment Disorder (PACS1-NDD) is a rare autosomal dominant disease caused by mutations in the PACS1 gene. To date, only 87 patients have been reported and, surprisingly, most of them carry the same variant (c.607C>T; p.R203W). The most relevant clinical features of the syndrome include neurodevelopment delay, seizures or a recognizable facial phenotype. Moreover, some of these characteristics overlap with other syndromes, such as the PACS2 or Wdr37 syndromes. The encoded protein phosphofurin acid cluster sorting 1 (PACS-1) is able to bind to different client proteins and direct them to their subcellular final locations. Therefore, although its main function is protein trafficking, it could perform other roles related to its client proteins. In patients with PACS1-NDD, a gain-of-function or a dominant negative mechanism for the mutated protein has been suggested. This, together with the fact that most of the patients carry the same genetic variant, makes it a good candidate for novel therapeutic approaches directed to decreasing the toxic effect of the mutated protein. Some of these strategies include the use of antisense oligonucleotides (ASOs) or targeting of its client proteins

Correlação entre o consumo de carboidratos e calorias com o desempenho físico de adolescentes praticantes de tênis

The practice of physical exercises leads to an increase in caloric expenditure and consequently to a greater daily energy requirement so that there is no fall in physical performance, especially when it comes to high performance athletes who have extensive and exhaustive training routines. Tennis is not an exception for such characteristics, as it is characterized by departures of various intensities and duration, with intermittent stimuli and repetitive movements. The aim of this study was to evaluate whether the carbohydrate intake and the daily energetic value that the athletes of tennis consumed had influence on the physical performance in aerobic power test. Eight tennis athletes, men, aged between 11 and 15, participated in the study. The following evaluations were performed: anthropometric (weight and height), body composition through electrical bioimpedance (BIA), a physical test (Yo-Yo Endurance Test Level 1) and finally an evaluation of food consumption (three hours on differentiated days, two being during the week and one at the end of the week). Subsequently, the variables were presented as mean and standard deviation. Athletes' body fat was 15.2 ± 4.8% while the estimated VO2 Max was 45.3 ± 5.8 ml / kg / min. When correlating the carbohydrate and calorie consumption with the VO2 Max of the athletes, no statistically significant values ​​were found. In summary, the athletes presented anthropometric data above the recommended for the sporting modality in question and adequate consumption for carbohydrates only, since calories, protein and lipids were above the recommendation.A prática de exercícios físicos leva a um aumento no gasto calórico e consequentemente a uma maior necessidade energética diária para que não haja queda no desempenho físico, principalmente quando se trata de atletas de alto rendimento, que possuem rotinas de treinos extensos e exaustivos. O tênis, não é uma exceção para tais características, pois caracteriza-se por partidas de diversas intensidades e duração, com estímulos intermitentes e movimentos repetitivos. O objetivo desta pesquisa foi avaliar se o consumo de carboidratos e o valor energético diário que os atletas de tênis consumiam tinham influência sobre o desempenho físico em teste de potência aeróbia. Participaram do estudo 8 atletas de tênis, homens, com faixa etária entre 11 e 15 anos. Foram realizadas as seguintes avaliações: antropométrica (Peso e Estatura), da composição corporal por meio da bioimpedância elétrica (BIA), um teste físico (Yo-Yo Endurance Teste Level 1) e por fim uma avaliação do consumo alimentar (três recordatórios de 24 horas em dias diferenciados, sendo dois durante a semana e um ao final de semana). Posteriormente as variáveis foram apresentadas em média e desvio padrão. A gordura corporal dos atletas foi 15,2 ± 4,8% enquanto o VO2 Max estimado foi 45,3 ± 5,8 ml/kg/min. Ao correlacionar o consumo de carboidrato e calorias com o VO2 Max dos atletas, não foram encontrados valores estatisticamente significantes. Em suma, verificou-se que os atletas apresentavam dados antropométricos acima do recomendado para a modalidade esportiva em questão e consumo adequado apenas para carboidratos, visto que calorias, proteína e lipídios estavam acima da recomendação

Evaluating face2gene as a tool to identify cornelia de lange syndrome by facial phenotypes

Characteristic or classic phenotype of Cornelia de Lange syndrome (CdLS) is associated with a recognisable facial pattern. However, the heterogeneity in causal genes and the presence of overlapping syndromes have made it increasingly difficult to diagnose only by clinical features. DeepGestalt technology, and its app Face2Gene, is having a growing impact on the diagnosis and management of genetic diseases by analysing the features of affected individuals. Here, we performed a phenotypic study on a cohort of 49 individuals harbouring causative variants in known CdLS genes in order to evaluate Face2Gene utility and sensitivity in the clinical diagnosis of CdLS. Based on the profile images of patients, a diagnosis of CdLS was within the top five predicted syndromes for 97.9% of our cases and even listed as first prediction for 83.7%. The age of patients did not seem to affect the prediction accuracy, whereas our results indicate a correlation between the clinical score and affected genes. Furthermore, each gene presents a different pattern recognition that may be used to develop new neural networks with the goal of separating different genetic subtypes in CdLS. Overall, we conclude that computer-assisted image analysis based on deep learning could support the clinical diagnosis of CdLS.Spanish Ministry of Science, Innovation and Universities/State Research Agency RTC-2017-6494-1; RTI2018-094434-B-I00 (MCIU/AEI/FEDER, UE) to P.G.-P.; Diputación General de Aragón - FEDER: European Social Fund [Grupo de Referencia B32_17R, to J.P.] as well as funds from the European JPIAMR-VRI network “CONNECT” to P.G.-P.; Medical Faculty of the University of Lübeck J09-2017 to I. P.; German Federal Ministry of Education and Research (BMBF

A Novel Intragenic Duplication in the HDAC8 Gene Underlying a Case of Cornelia de Lange Syndrome

Cornelia de Lange syndrome (CdLS) is a multisystemic genetic disorder characterized by distinctive facial features, growth retardation, and intellectual disability, as well as various systemic conditions. It is caused by genetic variants in genes related to the cohesin complex. Single-nucleotide variations are the best-known genetic cause of CdLS; however, copy number variants (CNVs) clearly underlie a substantial proportion of cases of the syndrome. The NIPBL gene was thought to be the locus within which clinically relevant CNVs contributed to CdLS. However, in the last few years, pathogenic CNVs have been identified in other genes such as HDAC8, RAD21, and SMC1A. Here, we studied an affected girl presenting with a classic CdLS phenotype heterozygous for a de novo ~32 kbp intragenic duplication affecting exon 10 of HDAC8. Molecular analyses revealed an alteration in the physiological splicing that included a 96 bp insertion between exons 9 and 10 of the main transcript of HDAC8. The aberrant transcript was predicted to generate a truncated protein whose accessibility to the active center was restricted, showing reduced ease of substrate entry into the mutated enzyme. Lastly, we conclude that the duplication is responsible for the patient’s phenotype, highlighting the contribution of CNVs as a molecular cause underlying CdLS

Evaluating Face2Gene as a Tool to Identify Cornelia de Lange Syndrome by Facial Phenotypes

Characteristic or classic phenotype of Cornelia de Lange syndrome (CdLS) is associated with a recognisable facial pattern. However, the heterogeneity in causal genes and the presence of overlapping syndromes have made it increasingly difficult to diagnose only by clinical features. DeepGestalt technology, and its app Face2Gene, is having a growing impact on the diagnosis and management of genetic diseases by analysing the features of affected individuals. Here, we performed a phenotypic study on a cohort of 49 individuals harbouring causative variants in known CdLS genes in order to evaluate Face2Gene utility and sensitivity in the clinical diagnosis of CdLS. Based on the profile images of patients, a diagnosis of CdLS was within the top five predicted syndromes for 97.9% of our cases and even listed as first prediction for 83.7%. The age of patients did not seem to affect the prediction accuracy, whereas our results indicate a correlation between the clinical score and affected genes. Furthermore, each gene presents a different pattern recognition that may be used to develop new neural networks with the goal of separating different genetic subtypes in CdLS. Overall, we conclude that computer-assisted image analysis based on deep learning could support the clinical diagnosis of CdL

Clinical relevance of postzygotic mosaicism in Cornelia de Lange syndrome and purifying selection of NIPBL variants in blood

Postzygotic mosaicism (PZM) in NIPBL is a strong source of causality for Cornelia de Lange syndrome (CdLS) that can have major clinical implications. Here, we further delineate the role of somatic mosaicism in CdLS by describing a series of 11 unreported patients with mosaic disease-causing variants in NIPBL and performing a retrospective cohort study from a Spanish CdLS diagnostic center. By reviewing the literature and combining our findings with previously published data, we demonstrate a negative selection against somatic deleterious NIPBL variants in blood. Furthermore, the analysis of all reported cases indicates an unusual high prevalence of mosaicism in CdLS, occurring in 13.1% of patients with a positive molecular diagnosis. It is worth noting that most of the affected individuals with mosaicism have a clinical phenotype at least as severe as those with constitutive pathogenic variants. However, the type of genetic change does not vary between germline and somatic events and, even in the presence of mosaicism, missense substitutions are located preferentially within the HEAT repeat domain of NIPBL. In conclusion, the high prevalence of mosaicism in CdLS as well as the disparity in tissue distribution provide a novel orientation for the clinical management and genetic counselling of families.Spanish Ministry of Health-ISCIII Fondo de Investigación Sanitaria (FIS) [Ref. PI19/01860, to F.J.R. and J.P.]; Diputación General de Aragón-FEDER: European Social Fund [Grupo de Referencia B32_17R / B32_20R, to J.P.]. A.L-P is supported by a “Juan de la Cierva-Incorporación” postdoctoral grant from MICIU (Spanish Ministry of Science and Universities