المؤلفون: V.E.F. Montaño, Susana Noval, B. Jimenez-Rolando, Rubén Martín-Arenas, Carlos Ibáñez, Elena Vallespín, J.C. Silla, A. del Pozo, I. Rosa-Perez, E. Mata Diaz

المصدر: Archivos de la Sociedad Española de Oftalmología (English Edition). 93:119-125

مصطلحات موضوعية: 0301 basic medicine, Genetics, genetic structures, biology, business.industry, ABCA4, General Medicine, Disease, Macular dystrophy, Bioinformatics, eye diseases, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Mutation (genetic algorithm), 030221 ophthalmology & optometry, biology.protein, Eye disorder, Medicine, Allelic heterogeneity, business, Gene, Exome sequencing

الوصف: Introduction Stargardt's disease is the most frequent form of inherited macular dystrophy in children and adults. It is a genetic eye disorder caused by mutations in ABCA4 gene with an autosomal recessive inheritance. ABCA4 is a very polymorphic and large gene containing 50 exons. The development of next generation sequencing (NGS) can be used for the genetic diagnosis of this disease. Patients and methods A report is presented on two patients with a clinical diagnosis of Stargardt's disease whose genetic confirmation was performed by a NGS panel of 298 genes. Results Clinically, the patients showed bull's eye maculopathy and absence of flecks, and genetically they shared the Gly1961Glu mutation that could explain their common phenotype, together with c.C3056T:p.T1019M for case 1, and c.287del:p.Asn96Thrfs*19 for case 2. Conclusions NGS is particularly useful in the diagnosis of Stargardt's disease as ABCA4 is a large gene with a high allelic heterogeneity that causes a wide range of clinical manifestations.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::02be75e675fff4d66365dbdec17804ceTest
https://doi.org/10.1016/j.oftale.2017.06.004Test

المؤلفون: Patricia Cruz, Pilar Santisteban, Darío Sanchez-Cabrero, María Palomares-Bralo, Veronica Pulido, Rocío Rosas, Alvaro García-Guede, Javier de Castro, Carmen Rodriguez, MDolores Diestro, Inmaculada Ibáñez de Cáceres, Carlos Rodriguez-Antolin, Olga Vera, Rubén Martín-Arenas, Olga Pernía, Ana Sastre-Perona

مصطلحات موضوعية: Cisplatin, molecular_biology, Tumor suppressor gene, In silico, Cell, Wnt signaling pathway, Transfection, Biology, Malignancy, medicine.disease, medicine.disease_cause, medicine.anatomical_structure, medicine, Cancer research, Carcinogenesis, medicine.drug

الوصف: SUMMARYDespite often leading to platinum resistance, platinum-based chemotherapy continues to be the standard treatment for many epithelial tumors. In this study we analyze the cytogenetic alterations that arise after cisplatin treatment providing novel insights into the molecular biology and the cellular mechanisms involved in the acquired resistance in these tumor types.MethodsIn this study, we used 1 million array-CGH and qRT-PCR methodologies to identify and validate cytogenetic alterations that arise after cisplatin treatment in four lung and ovarian paired cisplatin-sensitive/resistant cell lines. We used whole transcriptome sequencing (RNA-seq), functional transfection assays and gene-pathway activity analysis in our experimental cellular models and in fresh frozen primary NSCLC tumors to identify genes with a potential role in the development of this malignancy. Results were further explored in 55 lung and ovarian primary tumors and control samples and in two extensive in silico databases (TCGA and KMplotter) with 1,926 NSCLC and 1,425 additional epithelial tumors.ResultsLong-term cell exposure to platinum induces the frequent deletion ofITF2gene. Restoration ofITF2expression re-sensitizes tumor cells to platinum and recovers the levels of Wnt/β-catenin transcriptional activity.ITF2expression was also frequently downregulated in NSCLC, ovarian and other epithelial tumors, predicting a worse overall survival. We also identified an inverse correlation in expression betweenITF2andHOXD9, revealing that NSCLC patients with lower expression ofHOXD9have a better overall survival rate that was independent of the tumor histology.ConclusionWe have defined the implication ofITF2as a molecular mechanism behind the development of cisplatin resistance probably through the activation of the Wnt-signaling pathway. Our translational data suggest thatITF2could be used as a general epithelial tumor platinum-predictive marker and have identifiedHOXD9as a potential prognostic biomarker in NSCLC, a gene which expression is induced byWntsignaling. Furthermore, this data highlights the possible role ofITF2andHOXD9as a novel therapeutic target for platinum resistant tumors.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::71390574d6d5e4826928db3c9da80f8dTest
https://doi.org/10.1101/517169Test

المؤلفون: Lara, Rodriguez-Laguna, Noelia, Agra, Kristina, Ibañez, Gloria, Oliva-Molina, Gema, Gordo, Noor, Khurana, Devon, Hominick, María, Beato, Isabel, Colmenero, Gonzalo, Herranz, Juan M, Torres Canizalez, Rebeca, Rodríguez Pena, Elena, Vallespín, Rubén, Martín-Arenas, Ángela, Del Pozo, Cristina, Villaverde, Ana, Bustamante, Carmen, Ayuso, Pablo, Lapunzina, Juan C, Lopez-Gutierrez, Michael T, Dellinger, Victor, Martinez-Glez

المصدر: The Journal of Experimental Medicine

مصطلحات موضوعية: Adult, Male, Sirolimus, Adolescent, Class I Phosphatidylinositol 3-Kinases, TOR Serine-Threonine Kinases, Mutation, Missense, nutritional and metabolic diseases, Article, Lymphatic System, Amino Acid Substitution, Child, Preschool, Humans, lipids (amino acids, peptides, and proteins), Female, cardiovascular diseases, Lymphangioleiomyomatosis, Child, Proto-Oncogene Proteins c-akt, hormones, hormone substitutes, and hormone antagonists, Research Articles, Signal Transduction

الوصف: Generalized lymphatic anomaly (GLA) is a vascular disorder characterized by diffuse or multifocal lymphatic malformations (LMs). Here, Rodriguez-Laguna et al. report that somatic activating PIK3CA mutations can cause GLA, and we provide preclinical and clinical evidence to support the use of rapamycin for the treatment of GLA.
Generalized lymphatic anomaly (GLA) is a vascular disorder characterized by diffuse or multifocal lymphatic malformations (LMs). The etiology of GLA is poorly understood. We identified four distinct somatic PIK3CA variants (Glu542Lys, Gln546Lys, His1047Arg, and His1047Leu) in tissue samples from five out of nine patients with GLA. These same PIK3CA variants occur in PIK3CA-related overgrowth spectrum and cause hyperactivation of the PI3K–AKT–mTOR pathway. We found that the mTOR inhibitor, rapamycin, prevented lymphatic hyperplasia and dysfunction in mice that expressed an active form of PIK3CA (His1047Arg) in their lymphatics. We also found that rapamycin reduced pain in patients with GLA. In conclusion, we report that somatic activating PIK3CA mutations can cause GLA, and we provide preclinical and clinical evidence to support the use of rapamycin for the treatment of this disabling and deadly disease.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=pmid________::eebdb58195098c0d3268744e5876ca64Test
https://pubmed.ncbi.nlm.nih.gov/30591517Test

المؤلفون: Maria V. Gomez, Kristina Ibáñez, Fernando Santos-Simarro, Hector Gonzalez-Pecellin, Lara Rodriguez-Laguna, Ana Bustamante, Juan Carlos López-Gutiérrez, Cristina Villaverde, Elena Vallespín, Gema Gordo, Noelia Agra, Angela del Pozo, Pablo Lapunzina, Victor L. Ruiz-Perez, Julián Nevado, Victoria E. Fernandez-Montano, Sixto García-Miñaur, Carmen Ayuso, Rubén Martín-Arenas, Rocío Mena, Victor Martinez-Glez, Inmaculada Rueda-Arenas

المساهمون: Asociación Ultrafondo Solidario, Villarreal FC, Corporación de Radio y Televisión Española, Fundación Isabel Gemio, Instituto de Salud Carlos III, Federación Española de Enfermedades Neuromusculares, Federación Española de Enfermedades Raras, Fundación Conchita Rábago de Jiménez Díaz, Universidad Autónoma de Madrid

المصدر: Digital.CSIC. Repositorio Institucional del CSIC
instname

مصطلحات موضوعية: 0301 basic medicine, Adult, Male, Pathology, medicine.medical_specialty, Adolescent, Capillary malformation, Class I Phosphatidylinositol 3-Kinases, Somatic cell, 030105 genetics & heredity, Biology, Deep sequencing, CLAPO, Overgrowth, Arteriovenous Malformations, 03 medical and health sciences, Phosphatidylinositol 3-Kinases, medicine, Humans, Child, Lymphatic Diseases, Genetics (clinical), Genetic Association Studies, Retrospective Studies, Genetics, business.industry, Vascular malformation, High-Throughput Nucleotide Sequencing, PIK3CA, medicine.disease, Phenotype, Somatic mosaicism, Natural history, 030104 developmental biology, Lymphatic system, Mutation, Cohort, Vascular Disorder, Female, business

الوصف: [Purpose]: CLAPO syndrome is a rare vascular disorder characterized by capillary malformation of the lower lip, lymphatic malformation predominant on the face and neck, asymmetry, and partial/generalized overgrowth. Here we tested the hypothesis that, although the genetic cause is not known, the tissue distribution of the clinical manifestations in CLAPO seems to follow a pattern of somatic mosaicism.
[Methods]: We clinically evaluated a cohort of 13 patients with CLAPO and screened 20 DNA blood/tissue samples from 9 patients using high-throughput, deep sequencing.
[Results]: We identified five activating mutations in the PIK3CA gene in affected tissues from 6 of the 9 patients studied; one of the variants (NM_006218.2:c.248T>C; p.Phe83Ser) has not been previously described in developmental disorders.
[Conclusion]: We describe for the first time the presence of somatic activating PIK3CA mutations in patients with CLAPO. We also report an update of the phenotype and natural history of the syndrome.
This research was supported by the project “Genetics of vascular and lymphatic malformations” financed with funds donated by Asociación Ultrafondo and Villareal FC, cofinanced by project IP-17 from the funding call “Todos Somos Raros” (Telemaraton TVE promoted by Fundación Isabel Gemio, Federación ASEM, and Federación Española de Enfermedades Raras), cofinanced by the Instituto de Salud Carlos III, FEDER FUNDS FIS PI15/01481, and IIS-Fundación Jiménez Díaz UAM Genome Medicine Chair.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::650b41c7c89879fd045c7aa85fa20ea0Test
https://doi.org/10.1101/154591Test

المؤلفون: Maria Orera, María Ángeles Mori, Elena Vallespín, Chad R. Haldeman-Englert, Alberto Fernández-Jaén, Xia Li, Alberto Plaja, Lani Devaney, María Palomares-Bralo, Alicia Delicado, Rubén Martín-Arenas, Salmo Raskin, Stephanie E. Vallee, Esther Corbacho-Fernández, Rocío Mena, Miguel Del Campo, Jay W. Ellison, Holly Dubbs, Jill A. Rosenfeld, Fernando Santos-Simarro, Sixto García-Miñaur, Sulagna C. Saitta, Lluís Armengol, M. Carmen Crespo, Carlos A. Venegas-Vega, Inmaculada Rueda-Arenas, Jair Tenorio, Victoria E. Fernandez-Montano, Fernando Fernández-Ramírez, Karen W. Gripp, Blanca Marín Fernández, María Luisa de Torres, Pablo Lapunzina, Gordon C. Gowans, Elizabeth Denenberg, Julián Nevado, M Carmen Sanchez-Hombre, Mary Beth Dinulos, Duban B Bénédicte

المصدر: Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid
Consejería de Sanidad de la Comunidad de Madrid

مصطلحات موضوعية: Male, Microcephaly, Candidate gene, Developmental Disabilities, MAP Kinase Kinase 2, MAP2K2, Biology, Bioinformatics, Article, Gene duplication, Chromosome Duplication, Genetics, medicine, Humans, Megalencephaly, Child, Poly-ADP-Ribose Binding Proteins, Genetics (clinical), Macrocephaly, Infant, Syndrome, medicine.disease, Protein Inhibitors of Activated STAT, Hypotonia, DNA-Binding Proteins, Child, Preschool, Speech delay, Female, medicine.symptom, Chromosome Deletion, Chromosomes, Human, Pair 19, Transcription Factors

الوصف: Array comparative genomic hybridization (aCGH) is a powerful genetic tool that has enabled the identification of novel imbalances in individuals with intellectual disability (ID), autistic disorders and congenital malformations. Here we report a 'genotype first' approach using aCGH on 13 unrelated patients with 19p13.3 submicroscopic rearrangement (11 deletions and 2 duplications) and review cases in the literature and in public databases. Shared phenotypic features suggest that these patients represent an interstitial microdeletion/microduplication syndrome at 19p13.3. Common features consist of abnormal head circumference in most patients (macrocephaly with the deletions and microcephaly with the duplications), ID with developmental delay (DD), hypotonia, speech delay and common dysmorphic features. The phenotype is associated with at least a ~0.113 Mb critical region harboring three strong candidate genes probably associated with DD, ID, speech delay and other dysmorphic features: MAP2K2, ZBTB7A and PIAS4, an E3 ubiquitin ligase involved in the ubiquitin signaling pathways, which we hypothesize for the first time to be associated with head size in humans.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::acda0a94c6bcf36efa06bb9657b508d7Test
https://pubmed.ncbi.nlm.nih.gov/25853300Test

المؤلفون: Julián Nevado, María Palomares, Fiona Blanco-Kelly, Carmen Ayuso, Rubén Martín-Arenas, Camilo Vélez-Monsalve, María José Trujillo-Tiebas, Marta Corton, Cristina Villaverde, Pablo Lapunzina, I. Lorda-Sánchez, Elena Vallespín

المصدر: Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid
Consejería de Sanidad de la Comunidad de Madrid
PLoS ONE
PLoS ONE, Vol 12, Iss 2, p e0172363 (2017)

مصطلحات موضوعية: Male, 0301 basic medicine, PAX6 Transcription Factor, lcsh:Medicine, 030105 genetics & heredity, Medicine and Health Sciences, Blastomas, Deletions, lcsh:Science, Nephroblastoma, Aniridia, Oligonucleotide Array Sequence Analysis, Comparative Genomic Hybridization, Multidisciplinary, medicine.diagnostic_test, Chromosome Biology, Genomics, Chromosomal Aberrations, Oncology, Female, Chromosome Deletion, Research Article, congenital, hereditary, and neonatal diseases and abnormalities, WAGR syndrome, Computational biology, Chromosomes, Human Genomics, 03 medical and health sciences, WAGR Syndrome, Diagnostic Medicine, Genetics, medicine, Humans, Multiplex ligation-dependent probe amplification, Genetic testing, business.industry, Chromosomes, Human, Pair 11, lcsh:R, Breakpoint, Biology and Life Sciences, Computational Biology, Cancers and Neoplasms, Human Genetics, Cell Biology, Comparative Genomics, medicine.disease, eye diseases, Human genetics, 030104 developmental biology, Genetic Loci, lcsh:Q, sense organs, PAX6, business, Comparative genomic hybridization

الوصف: Chromosomal deletions at 11p13 are a frequent cause of congenital Aniridia, a rare pan-ocular genetic disease, and of WAGR syndrome, accounting up to 30% of cases. First-tier genetic testing for newborn with aniridia, to detect 11p13 rearrangements, includes Multiplex Ligation-dependent Probe Amplification (MLPA) and karyotyping. However, neither of these approaches allow obtaining a complete picture of the high complexity of chromosomal deletions and breakpoints in aniridia. Here, we report the development and validation of a customized targeted array-based comparative genomic hybridization, so called WAGR-array, for comprehensive high-resolution analysis of CNV in the WAGR locus. Our approach increased the detection rate in a Spanish cohort of 38 patients with aniridia, WAGR syndrome and other related ocular malformations, allowing to characterize four undiagnosed aniridia cases, and to confirm MLPA findings in four additional patients. For all patients, breakpoints were accurately established and a contiguous deletion syndrome, involving a large number of genes, was identified in three patients. Moreover, we identified novel microdeletions affecting 3' PAX6 regulatory regions in three families with isolated aniridia. This tool represents a good strategy for the genetic diagnosis of aniridia and associated syndromes, allowing for a more accurate CNVs detection, as well as a better delineation of breakpoints. Our results underline the clinical importance of performing exhaustive and accurate analysis of chromosomal rearrangements for patients with aniridia, especially newborns and those without defects in PAX6 after diagnostic screening.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4421ae058487536610c5c04b40bf1d4aTest
https://doi.org/10.1371/journal.pone.0172363Test

المؤلفون: Luis Fernández, Laura Casamayor Polo, María Bravo García‐Morato, Ana Belén Enguita Valls, Elena Ruiz‐Bravo, Patricia Muñoz‐Cabello, Kristina Ibáñez, Lara Rodríguez‐Laguna, Rubén Martín‐Arenas, Marta Ortega, María Palomares‐Bralo, Ángela Pozo, Luis García‐Guereta, Sixto García‐Miñaúr, Pablo Lapunzina, Elena Vallespín

الإتاحة: https://doi.org/10.1111/cge.13884/v2/response1Test