Crónica de un desencuentro: Le Corbusier en las Américas

[EN] The relationship between Le Corbusier and the American continent virtually encompasses his entire professional life. Embodied by about twenty transatlantic trips and a series of heterogeneous projects and buildings, this relationship was marked by frequent misunderstandings that conditioned the materialization of some of his projects. However, the significance of Le Corbusier’s work for the Americas, represented by two extraordinary buildings –the Curutchet House in Argentina and the Carpenter Center in the United States— and by a series of noteworthy projects that remained unbuilt, deserves special consideration. This article is dedicated to present an outline of the relationship and reciprocal misunderstanding between Le Corbusier and the American continent.[ES] La relación de Le Corbusier con el continente americano abarca virtualmente toda su vida activa. Plasmada en una veintena de viajes trasatlánticos y en un conjunto heterogéneo de propuestas, proyectos y obras, esta relación estuvo marcada por frecuentes malentendidos y desencuentros que condicionaron la concreción de algunos de sus proyectos. No obstante, el valor de su obra americana, representada por dos obras extraordinarias –la Casa Curutchet en Argentina y el Carpenter Center en Estados Unidos— y por una serie de proyectos notables que no llegaron a materializarse, merece un tratamiento específico. Este artículo está dedicado a presentar una síntesis de la relación y recíproco desencuentro entre Le Corbusier y el continente americano.Lapunzina, A. (2016). Crónica de un desencuentro: Le Corbusier en las Américas. En LE CORBUSIER. 50 AÑOS DESPUÉS. Editorial Universitat Politècnica de València. 1132-1147. https://doi.org/10.4995/LC2015.2015.985OCS1132114

Microhomology-mediated mechanisms underlie non-recurrent disease-causing microdeletions of the FOXL2 gene or its regulatory domain

Genomic disorders are often caused by recurrent copy number variations (CNVs), with nonallelic homologous recombination (NAHR) as the underlying mechanism. Recently, several microhomology-mediated repair mechanisms-such as microhomology-mediated end-joining (MMEJ), fork stalling and template switching (FoSTeS), microhomology-mediated break-induced replication (MMBIR), serial replication slippage (SRS), and break-induced SRS (BISRS)-were described in the etiology of non-recurrent CNVs in human disease. In addition, their formation may be stimulated by genomic architectural features. It is, however, largely unexplored to what extent these mechanisms contribute to rare, locus-specific pathogenic CNVs. Here, fine-mapping of 42 microdeletions of the FOXL2 locus, encompassing FOXL2 (32) or its regulatory domain (10), serves as a model for rare, locus-specific CNVs implicated in genetic disease. These deletions lead to blepharophimosis syndrome (BPES), a developmental condition affecting the eyelids and the ovary. For breakpoint mapping we used targeted array-based comparative genomic hybridization (aCGH), quantitative PCR (qPCR), long-range PCR, and Sanger sequencing of the junction products. Microhomology, ranging from 1 bp to 66 bp, was found in 91.7% of 24 characterized breakpoint junctions, being significantly enriched in comparison with a random control sample. Our results show that microhomology-mediated repair mechanisms underlie at least 50% of these microdeletions. Moreover, genomic architectural features, like sequence motifs, non-B DNA conformations, and repetitive elements, were found in all breakpoint regions. In conclusion, the majority of these microdeletions result from microhomology-mediated mechanisms like MMEJ, FoSTeS, MMBIR, SRS, or BISRS. Moreover, we hypothesize that the genomic architecture might drive their formation by increasing the susceptibility for DNA breakage or promote replication fork stalling. Finally, our locus-centered study, elucidating the etiology of a large set of rare microdeletions involved in a monogenic disorder, can serve as a model for other clustered, non-recurrent microdeletions in genetic disease

Mutations in the EXT1 and EXT2 genes in Spanish patients with multiple osteochondromas

Multiple osteochondromas is an autosomal dominant skeletal disorder characterized by the formation of multiple cartilage-capped tumours. Two causal genes have been identified, EXT1 and EXT2, which account for 65% and 30% of cases, respectively. We have undertaken a mutation analysis of the EXT1 and EXT2 genes in 39 unrelated Spanish patients, most of them with moderate phenotype, and looked for genotype-phenotype correlations. We found the mutant allele in 37 patients, 29 in EXT1 and 8 in EXT2. Five of the EXT1 mutations were deletions identified by MLPA. Two cases of mosaicism were documented. We detected a lower number of exostoses in patients with missense mutation versus other kinds of mutations. In conclusion, we found a mutation in EXT1 or in EXT2 in 95% of the Spanish patients. Eighteen of the mutations were novel.Fil: Sarrión, P.. Universidad de Barcelona; EspañaFil: Sangorrin, A.. Hospital Sant Joan de Déu; EspañaFil: Urreizti, R.. Universidad de Barcelona; EspañaFil: Delgado, María Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Córdoba; ArgentinaFil: Artuch, R.. Hospital Sant Joan de Déu; EspañaFil: Martorell, L.. Hospital Sant Joan de Déu; EspañaFil: Armstrong, J.. Hospital Sant Joan de Déu; EspañaFil: Anton, J.. Hospital Sant Joan de Déu; EspañaFil: Torner, F.. Hospital Sant Joan de Déu; EspañaFil: Vilaseca, M. A.. Hospital Sant Joan de Déu; EspañaFil: Nevado, J.. Hospital Universitario La Paz; EspañaFil: Lapunzina, P.. Hospital Universitario La Paz; EspañaFil: Asteggiano, Carla Gabriela. Universidad Nacional de Córdoba; Argentina. Universidad Católica de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Balcells, S.. Universidad de Barcelona; EspañaFil: Grinberg, D.. Universidad de Barcelona; Españ

Causes and Consequences of Multi-Locus Imprinting Disturbances in Humans.

Eight syndromes are associated with the loss of methylation at specific imprinted loci. There has been increasing evidence that these methylation defects in patients are not isolated events occurring at a given disease-associated locus but that some of these patients may have multi-locus imprinting disturbances (MLID) affecting additional imprinted regions. With the recent advances in technology, methylation profiling has revealed that imprinted loci represent only a small fraction of the methylation differences observed between the gametes. To figure out how imprinting anomalies occur at multiple imprinted domains, we have to understand the interplay between DNA methylation and histone modifications in the process of selective imprint protection during pre-implantation reprogramming, which, if disrupted, leads to these complex imprinting disorders (IDs).This is the author accepted manuscript. The final version is available from Cell Press (Elsevier) via http://dx.doi.org/10.1016/j.tig.2016.05.001

LC 150+

Descripció del recurs: 19 juliol 2023Text en anglès i castell

CIBERER: Spanish national network for research on rare diseases: A highly productive collaborative initiative

CIBER (Center for Biomedical Network Research; Centro de Investigacion Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mis sion is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low prevalence diseases, in line with the International Rare Diseases Research Consor tium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this arti cle, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Nephroblastomatosis or Wilms tumor in a fourth patient with a somatic PIK3CA mutation.

Wilms tumor and nephroblastomatosis are associated with syndromic conditions including hemihyperplasia. Hemihyperplasia is genetically heterogeneous and may be the result of genomic abnormalities seen in Beckwith-Wiedemann syndrome, mosaic chromosome or genomic abnormalities, or somatic point mutations. Somatic missense mutations affecting the PI3K-AKT-MTOR pathway result in segmental overgrowth and are present in numerous benign and malignant tumors. Here, we report a fourth patient with asymmetric overgrowth due to a somatic PIK3CA mutation who had nephroblastomatosis or Wilms tumor. Similar to two of three reported patients with a somatic PIK3CA mutation and renal tumors, he shared a PIK3CA mutation affecting codon 1047, presented at birth with asymmetric overgrowth, and had fibroadipose overgrowth. Codon 1047 is most commonly affected by somatic mutations in PIK3CA-related overgrowth spectrum (PROS). While the fibroadipose overgrowth phenotype appears to be common in individuals with PIK3CA mutations at codon 1047, individuals with a clinical diagnosis of Klippel-Trenaunay syndrome or isolated lymphatic malformation also had mutations affecting this amino acid. Screening for Wilms tumor in individuals with PROS-related hemihyperplasia may be considered and, until the natural history is fully elucidated in larger cohort studies, may follow guidelines for Beckwith-Wiedemann syndrome, or isolated hemihyperplasia. It is not known if the specific PIK3CA mutation, the mosaic distribution, or the clinical presentation affect the Wilms tumor or nephroblastomatosis risk in individuals with PROS. © 2016 Wiley Periodicals, Inc.US National Institutes of Health under NINDS grants K08NS092898This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1002/ajmg.a.3775

Phenotype-loci associations in networks of patients with rare disorders: application to assist in the diagnosis of novel clinical cases

Copy number variations (CNVs) are genomic structural variations (deletions, duplications, or translocations) that represent the 4.8–9.5% of human genome variation in healthy individuals. In some cases, CNVs can also lead to disease, being the etiology of many known rare genetic/genomic disorders. Despite the last advances in genomic sequencing and diagnosis, the pathological effects of many rare genetic variations remain unresolved, largely due to the low number of patients available for these cases, making it difficult to identify consistent patterns of genotype–phenotype relationships. We aimed to improve the identification of statistically consistent genotype–phenotype relationships by integrating all the genetic and clinical data of thousands of patients with rare genomic disorders (obtained from the DECIPHER database) into a phenotype–patient–genotype tripartite network. Then we assessed how our network approach could help in the characterization and diagnosis of novel cases in clinical genetics. The systematic approach implemented in this work is able to better define the relationships between phenotypes and specific loci, by exploiting large-scale association networks of phenotypes and genotypes in thousands of rare disease patients. The application of the described methodology facilitated the diagnosis of novel clinical cases, ranking phenotypes by locus specificity and reporting putative new clinical features that may suggest additional clinical follow-ups. In this work, the proof of concept developed over a set of novel clinical cases demonstrates that this network-based methodology might help improve the precision of patient clinical records and the characterization of rare syndromes

Co-occurrence of neurofibromatosis type 1 and optic nerve gliomas with autosomal dominant polycystic kidney disease type 2

Background: Autosomal dominant polycystic kidney disease (ADPKD) and neurofibromatosis type 1 (NF1) are both autosomal dominant disorders with a high rate of novel mutations. However, the two disorders have distinct and well-delineated genetic, biochemical, and clinical findings. Only a few cases of coexistence of ADPKD and NF1 in a single individual have been reported, but the possible implications of this association are unknown. Methods: We report an ADPKD male belonging to a family of several affected members in three generations associated with NF1 and optic pathway gliomas. The clinical diagnosis of ADPKD and NF1 was performed by several image techniques. Results: Linkage analysis of ADPKD family was consistent to the PKD2 locus by a nonsense mutation, yielding a truncated polycystin-2 by means of next-generation sequencing. The diagnosis of NF1 was confirmed by mutational analysis of this gene showing a 4-bp deletion, resulting in a truncated neurofibromin, as well. The impact of this association was investigated by analyzing putative genetic interactions and by comparing the evolution of renal size and function in the proband with his older brother with ADPKD without NF1 and with ADPKD cohorts. Conclusion: Despite the presence of both conditions there was not additive effect of NF1 and PKD2 in terms of the severity of tumor development and/or ADPKD progression.This study was financed in part by the Instituto de Salud Carlos III, the Ministerio de Ciencia y Innovación (EC08/00236) and the program for intensifying research activities (IdiPAZ and Agencia Lain Entralgo/CM) to R.P. or the program for intensifying (IdiPAZ and FIBHULP) to J.N. NF1 studies are supported by grants from Fundación Mutua Madrileña de Investigación Biomédica (FMM) and Asociación Española de Afectados de Neurofibromatosis. ISCIII RETIC REDINREN RD16/0009 FEDER Fund