Person: Marcos Alcalde, Íñigo
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First Name
Íñigo
Last Name
Marcos Alcalde
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Biotecnología
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Item Delineation of phenotypes and genotypes related to cohesin structural protein RAD21(Human Genetics, 2020) Krab, Lianne C.; Marcos Alcalde, Íñigo; Hennekam, Raoul C.Item MEPSAnd: Minimum Energy Path Surface Analysis over n-dimensional surfaces.(Bioinformatics, 2020) Marcos Alcalde, Íñigo; López Viñas, Eduardo; Gómez Puertas, PaulinoSummary: Understanding biophysical phenomena from the approach of molecular simulation is becoming the state-of-art in many research and technology development fields. Energy surfaces with more than 3 dimensions (2 coordinates and energy) are now computationally accessible, yet interpreting the information they offer is not straightforward and the tasks involved very time-consuming. Here we present MEPSAnd, an open source GUI-based program that natively calculates minimum energy paths across energy surfaces of an arbitrary number of dimensions. In addition to the multidimensional analysis of path through lowest barriers, MEPSAnd can also automatically calculate a finite series of suboptimal paths. To allow the efficient interpretation of results, MEPSAnd offers three distinct plotting solutions: i) energy profiles, ii) coordinate projections and iii) network projections. GUI-independent pipelines are also supported via direct python scripting. Therefore, MEPSAnd is a powerful user friendly tool that streamlines path-finding tasks on n-dimensional energy surfaces.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.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 Clinical relevance of postzygotic mosaicism in Cornelia de Lange syndrome and purifying selection of NIPBL variants in blood.(Scientific Reports, 2021) Latorre Pecillera, Ana; Gil Salvador, Marta; Parenti, Ilaria; Lucía Campos, Cristina; Trujillano, Laura; Marcos Alcalde, Íñigo; Arnedo, María; Ascaso, Ángela; Ayerza‑Casas, Ariadna; Antoñanzas Pérez, Rebeca; Gervasini, Cristina; Piccione, María; Marini, Milena; Weber, Axel; Kuechler, Alma; Bueno‑Lozano, Gloria; Gómez‑Puertas, Paulino; Kaiser, Frank J.; Pié, JuanPostzygotic 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.Item Novel Dominant KCNQ2 Exon 7 Partial In-Frame Duplication in a Complex Epileptic and Neurodevelopmental Delay Syndrome.(International Journal of Molecular Sciences, 2020) Lazo, Pedro A.; García, Juan L.; Gómez-Puertas, Paulino; Marcos Alcalde, Íñigo; Arjona, Cesar; Villarroel, Alvaro; González-Sarmiento, Rogelio; Fons, CarmenComplex neurodevelopmental syndromes frequently have an unknown etiology, in which genetic factors play a pathogenic role. This study utilizes whole-exome sequencing (WES) to examine four members of a family with a son presenting, since birth, with epileptic-like crises, combined with cerebral palsy, severe neuromotor and developmental delay, dystonic tetraparexia, axonal motor affectation, and hyper-excitability of unknown origin. The WES study detected within the patient a de novo heterozygous in-frame duplication of thirty-six nucleotides within exon 7 of the human KCNQ2 gene. This insertion duplicates the first twelve amino acids of the calmodulin binding site I. Molecular dynamics simulations of this KCNQ2 peptide duplication, modelled on the 3D structure of the KCNQ2 protein, suggest that the duplication may lead to the dysregulation of calcium inhibition of this protein function.Item The clinical and molecular spectrum of QRICH1 associated neurodevelopmental disorder.(Human Mutation: Variation, Informatics and Disease, 2021) Kumble, Smitha; Marcos Alcalde, Íñigo; Tümer, ZeynepDe novo variants in QRICH1 (Glutamine-rich protein 1) has recently been reported in 11 individuals with intellectual disability (ID). The function of QRICH1 is largely unknown but it is likely to play a key role in the unfolded response of endoplasmic reticulum stress through transcriptional control of proteostasis. In this study, we present 27 additional individuals and delineate the clinical and molecular spectrum of the individuals (n = 38) with QRICH1 variants. The main clinical features were mild to moderate developmental delay/ID (71%), nonspecific facial dysmorphism (92%) and hypotonia (39%). Additional findings included poor weight gain (29%), short stature (29%), autism spectrum disorder (29%), seizures (24%) and scoliosis (18%). Minor structural brain abnormalities were reported in 52% of the individuals with brain imaging. Truncating or splice variants were found in 28 individuals and 10 had missense variants. Four variants were inherited from mildly affected parents. This study confirms that heterozygous QRICH1 variants cause a neurodevelopmental disorder including short stature and expands the phenotypic spectrum to include poor weight gain, scoliosis, hypotonia, minor structural brain anomalies, and seizures. Inherited variants from mildly affected parents are reported for the first time, suggesting variable expressivity.Item Dysfunctional Homozygous VRK1-D263G Variant Impairs the Assembly of Cajal Bodies and DNA Damage Response in Hereditary Spastic Paraplegia.(Neurology Genetics, 2021) Morejón García, Patricia; Keren, Boris; Marcos Alcalde, Íñigo; Gómez Puertas, Paulino; Mochel, Fanny; Lazo, Pedro A.Background and Objectives To conduct a genetic and molecular functional study of a family with members affected of hereditary spastic paraplegia (HSP) of unknown origin and carrying a novel pathogenic vaccinia-related kinase 1 (VRK1) variant. Methods Whole-exome sequencing was performed in 2 patients, and their parents diagnosed with HSP. The novel VRK1 variant was detected by whole-exome sequencing, molecularly modeled and biochemically characterized in kinase assays. Functionally, we studied the role of this VRK1 variant in DNA damage response and its effect on the assembly of Cajal bodies (CBs). Results We have identified a very rare homozygous variant VRK1-D263G with a neurologic phenotype associated with HSP and moderate intellectual disability. The molecular modeling of this VRK1 variant protein predicted an alteration in the folding of a loop that interferes with the access to the kinase catalytic site. The VRK1-D263G variant is kinase inactive and does not phosphorylate histones H2AX and H3, transcription factors activating transcription factor 2 and p53, coilin needed for assembly of CBs, and p53 binding protein 1, a DNA repair protein. Functionally, this VRK1 variant protein impairs CB formation and the DNA damage response. Discussion This report expands the neurologic spectrum of neuromotor syndromes associated with a new and rare VRK1 variant, representing a novel pathogenic participant in complicated HSP and demonstrates that CBs and the DNA damage response are impaired in these patients.Item Pathogenic convergence of CNVs in genes functionally associated to a severe neuromotor developmental delay syndrome.(Human Genomics, 2021) García-Hernández, Juan L.; Corchete, Luis A.; Marcos Alcalde, Íñigo; Gómez Puertas, Paulino; Fons, Carmen; Lazo, Pedro A.Background Complex developmental encephalopathy syndromes might be the consequence of unknown genetic alterations that are likely to contribute to the full neurological phenotype as a consequence of pathogenic gene combinations. Methods To identify the additional genetic contribution to the neurological phenotype, we studied as a test case a boy, with a KCNQ2 exon-7 partial duplication, by single-nucleotide polymorphism (SNP) microarray to detect copy-number variations (CNVs). Results The proband presented a cerebral palsy like syndrome with a severe motor and developmental encephalopathy. The SNP array analysis detected in the proband several de novo CNVs, nine partial gene losses (LRRC55, PCDH9, NALCN, RYR3, ELAVL2, CDH13, ATP1A2, SLC17A5, ANO3), and two partial gene duplications (PCDH19, EFNA5). The biological functions of these genes are associated with ion channels such as calcium, chloride, sodium, and potassium with several membrane proteins implicated in neural cell-cell interactions, synaptic transmission, and axon guidance. Pathogenically, these functions can be associated to cerebral palsy, seizures, dystonia, epileptic crisis, and motor neuron dysfunction, all present in the patient. Conclusions Severe motor and developmental encephalopathy syndromes of unknown origin can be the result of a phenotypic convergence by combination of several genetic alterations in genes whose physiological function contributes to the neurological pathogenic mechanism.