Browsing by Author "Puisac, Beatriz"
Now showing 1 - 4 of 4
- Results Per Page
- Sort Options
Item Evaluating Face2Gene as a Tool to Identify Cornelia de Lange Syndrome by Facial Phenotypes.(International Journal of Molecular Sciences, 2020) Latorre Peciller, Ana; Ascaso, Ángela; Trujillano, Laura; Gil Salvador, Marta; Arnedo, María; Lucía Campos, Cristina; Antoñanzas Pérez, Rebeca; Marcos Alcalde, Íñigo; Parenti, Ilaria; Bueno Lozano, Gloria; Musio, Antonio; Puisac, Beatriz; Kaiser, Frank J.; Ramos, Feliciano J.; Gómez Puertas, Paulino; Pie, JuanCharacteristic 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 di cult 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 a ected 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 a ect the prediction accuracy, whereas our results indicate a correlation between the clinical score and a ected genes. Furthermore, each gene presents a di erent pattern recognition that may be used to develop new neural networks with the goal of separating di erent genetic subtypes in CdLS. Overall, we conclude that computer-assisted image analysis based on deep learning could support the clinical diagnosis of CdLS.Item Human Mitochondrial HMG-CoA Synthase Deficiency: Role of Enzyme Dimerization Surface and Characterization of Three New Patients.(International Journal of Molecular Sciences, 2018) Puisac, Beatriz; Marcos Alcalde, Íñigo; Hernández Marcos, María; Tobajas Morlana, Pilar; Levtova, Alina; C. Schwahn, Bernd; DeLaet, Corinne; Lace, Baiba; Gómez Puertas, Paulino; Pié, JuanMitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (mitochondrial HMG-CoA synthase deficiency or mHS deficiency, OMIM #605911) is an inborn error of metabolism that affects ketone body synthesis. Acute episodes include vomiting, lethargy, hepatomegaly, hypoglycemia and dicarboxylic aciduria. The diagnosis is difficult due to the relatively unspecific clinical and biochemical presentation, and fewer than 30 patients have been described. This work describes three new patients with mHS deficiency and two missense mutations c.334C>T (p.R112W) and c.430G>T (p.V144L) previously not reported. We developed a new method to express and measure the activity of the enzyme and in this work the study is extended to ten new missense variants including those of our patients. Enzymatic assays showed that three of the mutant proteins retained some but seven completely lacked activity. The identification of a patient homozygous for a mutation that retains 70% of enzyme activity opens the door to a new interpretation of the disease by demonstrating that a modest impairment of enzyme function can actually produce symptoms. This is also the first study employing molecular dynamics modelling of the enzyme mutations. We show that the correct maintenance of the dimerization surface is crucial for retaining the structure of the active center and therefore the activity of the enzyme.Item Things are not always what they seem: From Cornelia de Lange to KBG phenotype in a girl with genetic variants in NIPBL and ANKRD11.(Molecular Genetics and Genomic Medicine, 2021) Latorre-Pellicer, Ana; Ascaso, Ángela; Lucia-Campos, Cristina; Gil-Salvador, Marta; Arnedo, María; Antoñanzas, Rebeca; Ayerza-Casas, Ariadna; Marcos Alcalde, Íñigo; Gómez Puertas, Paulino; Ramos, Feliciano J.; Pié, Juan; Puisac, BeatrizItem Two-step ATP-driven opening of cohesin head.(Scientific Reports, 2017) Marcos Alcalde, Íñigo; Mendieta Moreno, Jesús I.; Puisac, Beatriz; Gil Rodríguez, María Concepción; Hernández Marcos, María; Soler Polo, Diego; Ramos, Feliciano J.; Ortega, José; Pié, Juan; Mendieta, Jesús; Gómez Puertas, PaulinoThe 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.