38 results on '"Pomares E"'
Search Results
2. EE656 A Cost-Utility Analysis of Avacopan for the Treatment of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis, a Rare Disease, in Spain
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Macía, M, primary, Romero Yuste, S, additional, Díaz, M, additional, Ramirez de Arellano Serna, A, additional, Jiménez Torres, M, additional, García Castells, A, additional, and Pomares, E, additional
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- 2022
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3. POSC46 A Cost-Effectiveness Analysis of Patiromer for the Treatment of Hyperkalemia in Spain
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Gonzalez-Juanatey, JR, primary, González-Franco, Á, additional, de-Sequera-Ortiz, P, additional, Valls, M, additional, Ramirez de Arellano Serna, A, additional, Pomares, E, additional, and Nieves, D, additional
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- 2022
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4. POSC161 Cost-Consequence Analysis of Rosuvastatin Versus Atorvastatin in the Spanish Setting
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Mata, P, primary, Cortés, X, additional, Martí, I, additional, Saborit-Canals, G, additional, and Pomares, E, additional
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- 2022
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5. PRO65 Time to Reimbursement for Orphan Drugs in EU5 in the Last FIVE YEARS
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Molchanova, E., primary, Benazet, F., additional, Vollmer, L., additional, Pomares, E., additional, Danev, V., additional, and Prada, M., additional
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- 2020
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6. PDB22 Cost-Effectiveness Analysis of Dapagliflozin in the Treatment of Type-2 Diabetes Mellitus in Spain
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Capel, M., primary, Pomares, E., additional, Pérez-Alcántara, F., additional, and Simón, S., additional
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- 2020
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7. PCN144 ECONOMIC EVALUATIONS OF CANCER INTERVENTIONS IN SPAIN: LITERATURE REVIEW
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Pomares, E., primary, Uría, E., additional, Cuesta, M., additional, and Brosa, M., additional
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- 2019
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8. The components of adult astigmatism and their age-related changes
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Hershko S, Lorenz K, von Trentini M, Pomares E, Corral M, Bataille L, Alio J, Rozema J, Jongenelen S, Ruiz-Hidalgo I, Tassignon M, Rauscher F, Blusch M, Dawczynski J, Wiedemann P, Mosca L, Guccione L, Riso M, Toro M, Rosati A, Duch F, Escude R, Martinez A, Morilla-Grasa A, Peris-Martinez C, Ajenjo A, Domene C, De Febrer M, Solans T, Gazdik A, Varssano D, Gold B, Toto L, Mastropasqua A, Mastropasqua L, Fasce F, Spinelli A, Knutsson K, Fogliato G, and EVICR net Project Gullstrand Study
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ocular refraction ,astigmatism ,ocular biometry - Abstract
Purpose To study the corneal and internal astigmatism and the age-related changes underlying the known refractive shift with-the-rule (WTR) towards against-the-rule (ATR) astigmatism. Methods Refractive and corneal biometry data were collected for a total of 1195 healthy Caucasian subjects, recruited by ophthalmological centres across Europe. After conversion of refractive and corneal surface astigmatism to power vectors J(0) and J(45), the total corneal and internal astigmatism were calculated. Results Both refractive power vectors had leptokurtic distributions with a narrow peak at zero, and a broader, secondary distribution at its base, corresponding to eyes without balanced components. This may be fitted with a bigaussian function (J(0): r(2) = 0.87; J(45): r(2) = 0.98). Statistically significant changes in these distributions are seen with age: for refractive J(0) the narrow peak shortens progressively, while the broad peak shifts positive from to negative values, corresponding to increased astigmatism and a shift from with-the-rule towards against-the-rule. For J(45) the narrow peak shortens with age as well, while the broad peak flattens. These changes in refractive J(0) result from statistically significant negative shifts in both the corneal and internal components with age (Kruskal-Wallis, p < 0.05). Conclusion In young participants corneal and internal astigmatism partially cancel each other out. This balance between both is gradually lost after age 50, leading to larger amounts of refractive astigmatism, as well as a reorientation of the axis. Given the small amplitude of these changes, they are unlikely to have repercussions for long term stability toric cataract or refractive surgery outcomes.
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- 2019
9. PHP34 - TIME ANALYSIS OF THE DRUG APPROVAL PROCESS IN EUROPE
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Martínez-Rodríguez, I., primary, Uría, E., additional, Pomares, E., additional, and Cuesta, M., additional
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- 2018
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10. PHP24 - ANALYSIS OF SPANISH THERAPEUTIC POSITIONING REPORTS PUBLISHED UNTIL 2017
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López, N., primary, Pomares, E., additional, and Cuesta, M., additional
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- 2018
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11. PSY106 - COST-EFFECTIVENESS OF RARE DISEASES IN SPAIN
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Pomares, E., primary, Uría, E., additional, Martínez-Rodríguez, I., additional, and Cuesta, M., additional
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- 2018
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12. Combined Genetic and High-Throughput Strategies for Molecular Diagnosis of Inherited Retinal Dystrophies
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De-Castro M, Pomares E, Lorés-Motta L, Tonda R, Dopazo J, Marfany G, and Gonzalez R
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Male ,Genetic Screens ,Genotype ,Science ,DNA Mutational Analysis ,Genetic Counseling ,Polymorphism, Single Nucleotide ,Molecular Genetics ,Genomic Medicine ,Autosomal Recessive ,Genetic Mutation ,Retinal Dystrophies ,Genetics ,Humans ,Inherited Eye Disorders ,Genetic Testing ,Genome Sequencing ,Biology ,Clinical Genetics ,Human Genetics ,Genomics ,X-Linked ,Pedigree ,Ophthalmology ,Haplotypes ,Molecular Diagnostic Techniques ,Autosomal Dominant ,Spain ,Genetics of Disease ,Mutation ,Retinal Disorders ,Medicine ,Female ,Research Article - Abstract
Most diagnostic laboratories are confronted with the increasing demand for molecular diagnosis from patients and families and the ever-increasing genetic heterogeneity of visual disorders. Concerning Retinal Dystrophies (RD), almost 200 causative genes have been reported to date, and most families carry private mutations. We aimed to approach RD genetic diagnosis using all the available genetic information to prioritize candidates for mutational screening, and then restrict the number of cases to be analyzed by massive sequencing. We constructed and optimized a comprehensive cosegregation RD-chip based on SNP genotyping and haplotype analysis. The RD-chip allows to genotype 768 selected SNPs (closely linked to 100 RD causative genes) in a single cost-, time-effective step. Full diagnosis was attained in 17/36 Spanish pedigrees, yielding 12 new and 12 previously reported mutations in 9 RD genes. The most frequently mutated genes were USH2A and CRB1. Notably, RD3-up to now only associated to Leber Congenital Amaurosis- was identified as causative of Retinitis Pigmentosa. The main assets of the RD-chip are: i) the robustness of the genetic information that underscores the most probable candidates, ii) the invaluable clues in cases of shared haplotypes, which are indicative of a common founder effect, and iii) the detection of extended haplotypes over closely mapping genes, which substantiates cosegregation, although the assumptions in which the genetic analysis is based could exceptionally lead astray. The combination of the genetic approach with whole exome sequencing (WES) greatly increases the diagnosis efficiency, and revealed novel mutations in USH2A and GUCY2D. Overall, the RD-chip diagnosis efficiency ranges from 16% in dominant, to 80% in consanguineous recessive pedigrees, with an average of 47%, well within the upper range of massive sequencing approaches, highlighting the validity of this time- and cost-effective approach whilst high-throughput methodologies become amenable for routine diagnosis in medium sized labs.
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- 2014
13. High-throughput approaches for the genetic diagnosis of retinal dystrophies
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Pomares E, Marfany G, and Gonzalez R
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- 2012
14. Nonsense-mediated decay as the molecular cause for autosomal recessive bestrophinopathy in two unrelated families
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Pomares E, Burés-Jelstrup A, Ruiz-Nogales S, Corcóstegui B, Gonzalez R, and Navarro R
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cardiovascular diseases ,urologic and male genital diseases ,female genital diseases and pregnancy complications - Abstract
To characterize the molecular basis of two novel BEST1 mutations causing autosomal recessive bestrophinopathy (ARB). Strong evidence argues in favor of the dominant negative effects of most autosomal dominantly inherited mutations, whereas there is only weak support for the molecular basis of the ARB phenotype.
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- 2012
15. High transcriptional complexity of the retinitis pigmentosa CERKL gene in human and mouse
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Garanto A, Riera M, Pomares E, Permanyer J, De-Castro M, Sava F, Abril JF, Marfany G, and Gonzalez R
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To shed light on the pathogenicity of the mutations in the retinitis pigmentosa gene CERKL, the authors aimed to characterize its transcriptional repertoire and focused on the use of distinct promoters and alternative splicing in human and mouse tissues.
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- 2011
16. Autosomal recessive retinitis pigmentosa with early macular affectation caused by premature truncation in PROM1
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Permanyer J, Navarro R, Friedman J, Pomares E, Castro-Navarro J, Marfany G, Swaroop A, and Gonzalez R
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congenital, hereditary, and neonatal diseases and abnormalities ,genetic structures ,sense organs ,eye diseases - Abstract
To identify the genetic basis of a large consanguineous Spanish pedigree affected with autosomal recessive retinitis pigmentosa (arRP) with premature macular atrophy and myopia.
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- 2010
17. Comprehensive SNP-chip for retinitis pigmentosa-Leber congenital amaurosis diagnosis: new mutations and detection of mutational founder effects
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Pomares E, Riera M, Permanyer J, Méndez P, Castro-Navarro J, Andrés-Gutiérrez A, Marfany G, and Gonzalez R
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Fast and efficient high-throughput techniques are essential for the molecular diagnosis of highly heterogeneous hereditary diseases, such as retinitis pigmentosa (RP). We had previously approached RP genetic testing by devising a chip based on co-segregation analysis for the autosomal recessive forms. In this study, we aimed to design a diagnostic tool for all the known genes (40 up to now) responsible for the autosomal dominant and recessive RP and Leber congenital amaurosis (LCA). This new chip analyzes 240 single nucleotide polymorphisms (SNPs) (6 per gene) on a high-throughput genotyping platform (SNPlex, Applied Biosystems), and genetic diagnosis is based on the co-segregation analysis of SNP haplotypes in independent families. In a single genotyping step, the number of RP candidates to be screened for mutations is considerably reduced, and in the most informative families, all the candidates are ruled out at once. In a panel of RP Spanish pedigrees, the disease chip became a crucial tool for selecting those suitable for genome-wide RP gene search, and saved the burdensome direct mutational screening of every known RP gene. In a large adRP family, the chip allowed ruling out of all but the causative gene, and identification of an unreported null mutation (E181X) in PRPF31. Finally, on the basis of the conservation of the SNP haplotype linked to this pathogenic variant, we propose that the E181X mutation spread through a cohort of geographically isolated families by a founder effect.
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- 2010
18. Identification of an intronic single-point mutation in RP2 as the cause of semidominant X-linked retinitis pigmentosa
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Pomares E, Riera M, Castro-Navarro J, Andrés-Gutiérrez A, Gonzalez R, and Marfany G
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sense organs ,eye diseases - Abstract
A large family with 11 males and 2 females with X-linked retinitis pigmentosa (XLRP) was analyzed in search of pathologic mutations.
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- 2009
19. Novel high-throughput SNP genotyping cosegregation analysis for genetic diagnosis of autosomal recessive retinitis pigmentosa and Leber congenital amaurosis
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Pomares E, Marfany G, Brión MJ, Carracedo A, and Gonzalez R
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genetic structures ,eye diseases - Abstract
Retinitis pigmentosa (RP), the major cause of blindness in adults, is an extremely heterogeneous monogenic disorder. More than 32 causative genes have been identified, 18 of which are involved in autosomal recessive RP (arRP); however, more than 50% of the cases remain unassigned. There are no major causative genes identified for arRP nor any prevalent mutations, which make mutational screening of the already reported RP genes extremely time consuming and costly. Nonetheless, this step is unavoidable for genetic diagnosis of patients and potential carriers, and it is a prerequisite before approaching the identification of new RP genes and loci. We have designed an innovative high-throughput time- and cost-effective strategy for cosegregation analysis of 22 genes of arRP and Leber congenital amaurosis (LCA; an autosomal recessive retinal dystrophy that shares some of the RP genes and traits) by SNP genotyping. This novel indirect method has been validated in a panel of 54 consanguineous and nonconsanguineous arRP families. In a single and fast genotyping step: 1) we discarded all the 22 candidate genes in 13% of the pedigrees, highlighting the families of choice to search for novel arRP genes/loci; 2) we excluded an average of 18-19 genes per family, thus diminishing the number of genes to screen for pathogenic mutations; and 3) we identified CERKL as the causative RP gene in a family in which this candidate had been previously discarded by microsatellite cosegregation analysis. This type of approach can also be applied to other nonretinal diseases with high genetic heterogeneity, such as hereditary deafness or Parkinson disease.
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- 2007
20. Functional implications of the presenilin dimerization: reconstitution of gamma-secretase activity by assembly of a catalytic site at the dimer interface of two catalytically inactive presenilins
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Cervantes S, Saura CA, Pomares E, Gonzalez R, and Marfany G
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mental disorders ,nervous system diseases - Abstract
Presenilins are the catalytic components of gamma-secretase, an intramembrane-cleaving protease whose substrates include beta-amyloid precursor protein (betaAPP) and the Notch receptors. These type I transmembrane proteins undergo two distinct presenilin-dependent cleavages within the transmembrane region, which result in the production of Abeta and APP intracellular domain (from betaAPP) and the Notch intracellular domain signaling peptide. Most cases of familial Alzheimer's disease are caused by presenilin mutations, which are scattered throughout the coding sequence. Although the underlying molecular mechanism is not yet known, the familial Alzheimer's disease mutations produce a shift in the ratio of the long and short forms of the Abeta peptide generated by the gamma-secretase. We and others have previously shown that presenilin homodimerizes and suggested that a presenilin dimer is at the catalytic core of gamma-secretase. Here, we demonstrate that presenilin transmembrane domains contribute to the formation of the dimer. In-frame substitution of the hydrophilic loop 1, located between transmembranes I and II, which modulates the interactions within the N-terminal fragment/N-terminal fragment dimer, abolishes both presenilinase and gamma-secretase activities. In addition, by reconstituting gamma-secretase activity from two catalytically inactive presenilin aspartic mutants, we provide evidence of an active diaspartyl group assembled at the interface between two presenilin monomers. Under our conditions, this catalytic group mediates the generation of APP intracellular domain and Abeta but not Notch intracellular domain, therefore suggesting that specific diaspartyl groups within the presenilin catalytic core of gamma-secretase mediate the cleavage of different substrates.
- Published
- 2004
21. Union makes strength: a worldwide collaborative genetic and clinical study to provide a comprehensive survey of RD3 mutations and delineate the associated phenotype
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Bernd Wissinger, Renate C. Zekveld-Vroon, Alejandro Estrada-Cuzcano, Sandro Banfi, Jean-Michel Rozet, Ditta Zobor, Esther Pomares, Isabelle Perrault, Huanan Ren, Shiqiang Li, Susanne Kohl, Frans P.M. Cremers, André Mégarbané, Anneke I. den Hollander, Ralph J. Florijn, Rui Chen, Marc Jeanpierre, Irma Lopez, Francesco Testa, Nisrine Aboussair, Roser Gonzàlez-Duarte, Blanca C. Flores, Corinne Leowski, Francesca Simonelli, Edwin M. Stone, Josseline Kaplan, Qingjiong Zhang, Catherine Edelson, Arthur A.B. Bergen, Jean Andorf, Arnold Munnich, Cristina Villanueva, Nathalie Delphin, Robert K. Koenekoop, Xia Wang, Universitat de Barcelona, Perrault, I, Estrada Cuzcano, A, Lopez, I, Kohl, S, Li, S, Testa, Francesco, Zekveld Vroon, R, Wang, X, Pomares, E, Andorf, J, Aboussair, N, Banfi, Sandro, Delphin, N, den Hollander, Ai, Edelson, C, Florijn, R, Jean Pierre, M, Leowski, C, Megarbane, A, Villanueva, C, Flores, B, Munnich, A, Ren, H, Zobor, D, Bergen, A, Chen, R, Cremers, Fp, Gonzalez Duarte, R, Koenekoop, Rk, Simonelli, Francesca, Stone, E, Wissinger, B, Zhang, Q, Kaplan, J, Rozet, Jm, Human Genetics, ANS - Amsterdam Neuroscience, and ARD - Amsterdam Reproduction and Development
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Male ,Retinal degeneration ,Photoreceptors ,Genetic Screens ,genetic structures ,Genetics and epigenetic pathways of disease [NCMLS 6] ,Leber Congenital Amaurosis ,lcsh:Medicine ,Social and Behavioral Sciences ,medicine.disease_cause ,Linkage Disequilibrium ,Fotoreceptors ,Cohort Studies ,0302 clinical medicine ,Sociology ,Human Families ,lcsh:Science ,Child ,Genetics ,0303 health sciences ,Mutation ,Multidisciplinary ,Retinal Degeneration ,Pedigree ,3. Good health ,Europe ,Phenotype ,Child, Preschool ,Medicine ,Retinal Disorders ,GUCY2D ,Female ,Research Article ,Adult ,Canada ,China ,Adolescent ,Nonsense mutation ,Genetic Counseling ,Biology ,Retina ,Frameshift mutation ,Young Adult ,03 medical and health sciences ,Genetic Mutation ,medicine ,Humans ,Allele ,Eye Proteins ,030304 developmental biology ,Polymorphism, Genetic ,lcsh:R ,Mutació (Biologia) ,Infant ,Human Genetics ,Heterozygote advantage ,Mutation (Biology) ,medicine.disease ,United States ,eye diseases ,Ophthalmology ,Genetics of Disease ,Genetic Polymorphism ,Pediatric Ophthalmology ,030221 ophthalmology & optometry ,lcsh:Q ,sense organs ,Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6] ,Population Genetics ,Founder effect - Abstract
Contains fulltext : 117915.pdf (Publisher’s version ) (Open Access) Leber congenital amaurosis (LCA) is the earliest and most severe retinal degeneration (RD), and the most common cause of incurable blindness diagnosed in children. It is occasionally the presenting symptom of multisystemic ciliopathies which diagnosis will require a specific care of patients. Nineteen LCA genes are currently identified and three of them account for both non-syndromic and syndromic forms of the disease. RD3 (LCA12) was implicated as a LCA gene based on the identification of homozygous truncating mutations in two LCA families despite the screening of large cohorts of patients. Here we provide a comprehensive survey of RD3 mutations and of their clinical expression through the screening of a cohort of 852 patients originating worldwide affected with LCA or early-onset and severe RD. We identified three RD3 mutations in seven unrelated consanguineous LCA families - i.e., a 2 bp deletion and two nonsense mutations - predicted to cause complete loss of function. Five families originating from the Southern Shores of the Mediterranean segregated a similar mutation (c.112C>T, p.R38*) suggesting that this change may have resulted from an ancient founder effect. Considering the low frequency of RD3 carriers, the recurrence risk for LCA in non-consanguineous unions is negligible for both heterozygote and homozygote RD3 individuals. The LCA12 phenotype in our patients is highly similar to those of patients with mutant photoreceptor-specific guanylate cyclase (GUCY2D/LCA1). This observation is consistent with the report of the role of RD3 in trafficking of GUCYs and gives further support to a common mechanism of photoreceptor degeneration in LCA12 and LCA1, i.e., inability to increase cytoplasmic cGMP concentration in outer segments and thus to recover the dark-state. Similar to LCA1, LCA12 patients have no extraocular symptoms despite complete inactivation of both RD3 alleles, supporting the view that extraocular investigations in LCA infants with RD3 mutations should be avoided.
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- 2013
22. Efficient correction of ABCA4 variants by CRISPR-Cas9 in hiPSCs derived from Stargardt disease patients.
- Author
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Siles L, Ruiz-Nogales S, Navinés-Ferrer A, Méndez-Vendrell P, and Pomares E
- Abstract
Inherited retinal dystrophies comprise a broad group of genetic eye diseases without effective treatment. Among them, Stargardt disease is the second most prevalent pathology. This pathology triggers progressive retinal degeneration and vision loss in children and adults. In recent years, the evolution of several genome editing technologies, such as the CRISPR-Cas9 system, has revolutionized disease modeling and personalized medicine. Human induced pluripotent stem cells also provide a valuable tool for in vitro disease studies and therapeutic applications. Here, we show precise correction of two ABCA4 pathogenic variants in human induced pluripotent stem cells from two unrelated patients affected with Stargardt disease. Gene editing was achieved with no detectable off-target genomic alterations, demonstrating efficient ABCA4 gene correction without deleterious effects. These results will contribute to the development of emerging gene and cell therapies for inherited retinal dystrophies., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)
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- 2023
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23. High-Efficiency CRISPR/Cas9-Mediated Correction of a Homozygous Mutation in Achromatopsia-Patient-Derived iPSCs.
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Siles L, Gaudó P, and Pomares E
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- Humans, Mutation, Transcription Activator-Like Effector Nucleases genetics, Induced Pluripotent Stem Cells, Color Vision Defects genetics, Color Vision Defects therapy, CRISPR-Cas Systems, Gene Editing methods
- Abstract
Achromatopsia is an autosomal recessive disorder, in which cone photoreceptors undergo progressive degeneration, causing color blindness and poor visual acuity, among other significant eye affectations. It belongs to a group of inherited retinal dystrophies that currently have no treatment. Although functional improvements have been reported in several ongoing gene therapy studies, more efforts and research should be carried out to enhance their clinical application. In recent years, genome editing has arisen as one of the most promising tools for personalized medicine. In this study, we aimed to correct a homozygous PDE6C pathogenic variant in hiPSCs derived from a patient affected by achromatopsia through CRISPR/Cas9 and TALENs technologies. Here, we demonstrate high efficiency in gene editing by CRISPR/Cas9 but not with TALENs approximation. Despite a few of the edited clones displaying heterozygous on-target defects, the proportion of corrected clones with a potentially restored wild-type PDE6C protein was more than half of the total clones analyzed. In addition, none of them presented off-target aberrations. These results significantly contribute to advances in single-nucleotide gene editing and the development of future strategies for the treatment of achromatopsia.
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- 2023
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24. Impaired Bestrophin Channel Activity in an iPSC-RPE Model of Best Vitelliform Macular Dystrophy (BVMD) from an Early Onset Patient Carrying the P77S Dominant Mutation.
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Navinés-Ferrer A, Ruiz-Nogales S, Navarro R, and Pomares E
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- Chloride Channels genetics, Chloride Channels metabolism, Eye Proteins genetics, Eye Proteins metabolism, Humans, Mutation, Retinal Pigment Epithelium metabolism, Bestrophins genetics, Bestrophins metabolism, Induced Pluripotent Stem Cells metabolism, Vitelliform Macular Dystrophy genetics, Vitelliform Macular Dystrophy metabolism, Vitelliform Macular Dystrophy pathology
- Abstract
Best Vitelliform Macular dystrophy (BVMD) is the most prevalent of the distinctive retinal dystrophies caused by mutations in the BEST1 gene. This gene, which encodes for a homopentameric calcium-activated ion channel, is crucial for the homeostasis and function of the retinal pigment epithelia (RPE), the cell type responsible for recycling the visual pigments generated by photoreceptor cells. In BVMD patients, mutations in this gene induce functional problems in the RPE cell layer with an accumulation of lipofucsin that evolves into cell death and loss of sight. In this work, we employ iPSC-RPE cells derived from a patient with the p.Pro77Ser dominant mutation to determine the correlation between this variant and the ocular phenotype. To this purpose, gene and protein expression and localization are evaluated in iPSC-RPE cells along with functional assays like phagocytosis and anion channel activity. Our cell model shows no differences in gene expression, protein expression/localization, or phagocytosis capacity, but presents an increased chloride entrance, indicating that the p.Pro77Ser variant might be a gain-of-function mutation. We hypothesize that this variant disturbs the neck region of the BEST1 channel, affecting channel function but maintaining cell homeostasis in the short term. This data shed new light on the different phenotypes of dominant mutations in BEST1 , and emphasize the importance of understanding its molecular mechanisms. Furthermore, the data widen the knowledge of this pathology and open the door for a better diagnosis and prognosis of the disease.
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- 2022
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25. Cost-effectiveness analysis of dapagliflozin for the treatment of type 2 diabetes mellitus in Spain: results of the DECLARE-TIMI 58 study.
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Escobar C, Morales C, Capel M, Simón S, Pérez-Alcántara F, and Pomares E
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- Adult, Benzhydryl Compounds, Cost-Benefit Analysis, Glucosides, Humans, Hypoglycemic Agents therapeutic use, Prospective Studies, Quality-Adjusted Life Years, Spain epidemiology, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 epidemiology
- Abstract
Background: The objective of this study was to carry out a cost-effectiveness analysis of dapagliflozin, as an add-on therapy to standard of care (SoC), for the treatment of type 2 diabetes mellitus (T2DM) in Spain, based on the results of the DECLARE-TIMI 58 trial., Methods: A discrete event simulation model (Cardiff T2DM) based on the data observed in the DECLARE-TIMI 58 trial was adapted to the Spanish setting to estimate the costs and health outcomes of treatment with dapagliflozin in patients with T2DM who had or were at risk of atherosclerotic cardiovascular disease. Macrovascular events (hospitalization for heart failure, myocardial infarction, stroke, and unstable angina), end-stage renal disease and cardiovascular and non-cardiovascular mortality were modeled according to the survival equations of the DECLARE-TIMI 58 study. Microvascular events (blindness and ulcers) were estimated based on the risk equations of the UK Prospective Diabetes Study. The analysis was conducted from the Spanish National Health System perspective and the time horizon was 30 years. The results were evaluated in terms of cost per quality-adjusted life year (QALY) gained. Only direct health costs were included, and a 3% discount rate was applied to costs and health outcomes. Univariate and probabilistic sensitivity analyses (PSA) were made to assess the robustness of the results., Results: In the main analysis, dapagliflozin was a dominant therapeutic option compared with placebo, with greater effectiveness (0.08 QALYs) and lower associated total costs per patient (€ -2,921). The univariate sensitivity analysis and the PSA confirmed the robustness of the results. The PSA showed the probability that dapagliflozin was a dominant alternative compared with placebo was 84.2% and that it was cost-effective of 92.1%, under a willingness-to-pay of € 20,000/QALY gained., Conclusions: The analysis of data from the DECLARE-TIMI 58 trial shows that dapagliflozin would be a cost-effective option in Spain for the treatment of adult patients with T2DM, as an add-on therapy to SoC, compared with placebo., (© 2022. The Author(s).)
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- 2022
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26. A cost-effectiveness analysis of patiromer for the treatment of hyperkalemia in chronic kidney disease patients with and without heart failure in Spain.
- Author
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González-Juanatey JR, González-Franco Á, de Sequera P, Valls M, Ramirez de Arellano A, Pomares E, and Nieves D
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- Cost-Benefit Analysis, Humans, Polymers, Spain, Heart Failure complications, Heart Failure drug therapy, Hyperkalemia drug therapy, Hyperkalemia etiology, Renal Insufficiency, Chronic
- Abstract
Aims: Renin-angiotensin-aldosterone system inhibitors (RAASi) therapy is commonly used to reduce the risk of death and to slow down disease progression in patients with chronic kidney disease (CKD), heart failure (HF) and hypertension. However, the cardio-renal benefits of RAASi therapy are also associated with an increased risk of hyperkalemia (HK), which may lead to dose reduction or discontinuation of therapy. Patiromer has demonstrated to reduce the risk of HK, which enables to maintain optimal doses of RAASi therapy. This study aimed to assess the cost-effectiveness of patiromer for the management of HK in CKD patients with and without HF in Spain., Methods: A Markov model was developed to evaluate the costs and benefits of patiromer for the management of HK in patients with CKD stages 3-4 with and without HF treated with RAASi over a lifetime horizon. The main outcomes included total direct costs (€2021), quality-adjusted life-years (QALYs), life-years gained (LYG) and incremental cost-effectiveness ratio (ICER). Deterministic one-way and probabilistic sensitivity analyses were performed to assess the robustness of the results., Results: Patiromer was more effective compared to no patiromer (5.76 vs 5.57 QALYs; 7.73 vs 7.50 LYG), and resulted in an incremental cost of €3,574, yielding an ICER of €19,092/QALY gained and of €15,236/LYG. Sensitivity analyses suggested that the results were robust to changes in most input parameters., Conclusions: Patiromer is a cost-effective intervention in maintaining normokalemia and enabling optimal RAASi therapy in patients with CKD stages 3-4 with and without HF in Spain.
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- 2022
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27. New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform.
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Abad-Morales V, Wert A, Ruiz Gómez MÁ, Navarro R, and Pomares E
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- Child, Preschool, Female, Hearing Loss, Sensorineural complications, Hearing Loss, Sensorineural genetics, Heterozygote, Humans, Intellectual Disability complications, Intellectual Disability genetics, Leber Congenital Amaurosis complications, Leber Congenital Amaurosis genetics, Male, Mutation, Osteochondrodysplasias complications, Osteochondrodysplasias genetics, Pedigree, Protein Isoforms, Hearing Loss, Sensorineural pathology, Intellectual Disability pathology, Leber Congenital Amaurosis pathology, Nicotinamide-Nucleotide Adenylyltransferase genetics, Osteochondrodysplasias pathology
- Abstract
This study aims to genetically characterize a two-year-old patient suffering from multiple systemic abnormalities, including skeletal, nervous and developmental involvements and Leber congenital amaurosis (LCA). Genetic screening by next-generation sequencing identified two heterozygous pathogenic variants in nicotinamide mononucleotide adenylyltransferase 1 ( NMNAT1 ) as the molecular cause of the disease: c.439+5G>T and c.299+526_*968dup.This splice variant has never been reported to date, whereas pathogenic duplication has recently been associated with cases displaying an autosomal recessive disorder that includes a severe form of spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and LCA (SHILCA), as well as some brain anomalies. Our patient presented clinical manifestations which correlated strongly with this reported syndrome. To further study the possible transcriptional alterations resulting from these mutations, mRNA expression assays were performed in the patient and her father. The obtained results detected aberrant alternative transcripts and unbalanced levels of expression, consistent with severe systemic involvement. Moreover, these analyses also detected a novel NMNAT1 isoform, which is variably expressed in healthy human tissues. Altogether, these findings represent new evidence of the correlation of NMNAT1 and SHILCA syndrome, and provide additional insights into the healthy and pathogenic expression of this gene.
- Published
- 2021
- Full Text
- View/download PDF
28. Identification of a novel homozygous ARSG mutation as the second cause of Usher syndrome type 4.
- Author
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Abad-Morales V, Navarro R, Burés-Jelstrup A, and Pomares E
- Abstract
Purpose: Usher syndrome is a genetic disease characterized by combined sensorineural hearing loss, retinitis pigmentosa, and vestibular areflexia, with 15 known causative genes. Depending on the severity and onset of the symptoms, 3 different subtypes of the pathology have been classically established, although an increasing number of rare cases are being accumulated as atypical forms. The present work aims to discover the genetic cause in a patient with atypical Usher syndrome, by performing whole exome sequencing in several family members., Observations: The obtained results identified a novel homozygous missense mutation (p.Asp44Asn) in the ARSG gene as the cause of the disease, which was characterized by late-onset progressive symptoms in the patient. A resembling phenotype, recently defined as the novel Usher syndrome type 4, was described in three families sharing another ARSG mutation. Both mutations affect two contiguous amino acid residues, which appear to be critical for the correct function of the protein., Conclusions and Importance: These findings support the identification of the second disease mutation in this gene and a new evidence of the implication of ARSG in the genetic basis of Usher syndrome type 4., Competing Interests: The following authors have no financial disclosures: VA-M, RN, AB-J, and EP., (© 2020 The Authors.)
- Published
- 2020
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29. Generation of Best disease-derived induced pluripotent stem cell line (FRIMOi006-A) carrying a novel dominant mutation in BEST1 gene.
- Author
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Domingo-Prim J, Riera M, Abad-Morales V, Ruiz-Nogales S, Corcostegui B, and Pomares E
- Subjects
- Adult, Bestrophins metabolism, Cell Differentiation, Cell Line metabolism, Cells, Cultured, Female, Fibroblasts cytology, Fibroblasts metabolism, Humans, Induced Pluripotent Stem Cells cytology, Mutation, Vitelliform Macular Dystrophy metabolism, Vitelliform Macular Dystrophy physiopathology, Bestrophins genetics, Cell Line cytology, Induced Pluripotent Stem Cells metabolism, Vitelliform Macular Dystrophy genetics
- Abstract
Best disease, also known as Best vitelliform macular dystrophy, is an autosomal dominant form of macular degeneration. Here, we have generated an induced pluripotent stem cell (iPSC) line derived from a Best disease patient carrying a new dominant mutation in the BEST1 gene. Skin fibroblasts were reprogrammed to iPSCs by the non-integrative Sendai-virus method. The iPSC line has been characterized preserving the BEST1 mutation, expressing the pluripotency markers and being capable to differentiate to endoderm, mesoderm and ectoderm in vitro., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2019
- Full Text
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30. Generation of an induced pluripotent stem cell line (FRIMOi007-A) derived from an incomplete achromatopsia patient carrying a novel homozygous mutation in PDE6C gene.
- Author
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Domingo-Prim J, Abad-Morales V, Riera M, Navarro R, Corcostegui B, and Pomares E
- Subjects
- Adult, Cell Differentiation, Cell Line metabolism, Cells, Cultured, Color Vision Defects metabolism, Color Vision Defects physiopathology, Cyclic Nucleotide Phosphodiesterases, Type 6 metabolism, Eye Proteins metabolism, Fibroblasts cytology, Fibroblasts metabolism, Genetic Diseases, X-Linked metabolism, Genetic Diseases, X-Linked physiopathology, Homozygote, Humans, Induced Pluripotent Stem Cells cytology, Male, Mutation, Cell Line cytology, Color Vision Defects genetics, Cyclic Nucleotide Phosphodiesterases, Type 6 genetics, Eye Proteins genetics, Genetic Diseases, X-Linked genetics, Induced Pluripotent Stem Cells metabolism
- Abstract
Incomplete achromatopsia (ACHM) is a disorder in which there is function defect of cone photoreceptors in the retina and individuals with such disease retain residual color vision. Here, we have generated an induced pluripotent stem cell (iPSC) line carrying a homozygous mutation in the PDE6C gene, already related with this vision disorder. Skin fibroblasts from a patient with incomplete ACHM were reprogrammed to iPSCs by the non-integrative Sendai-virus method. Finally, the iPSC line has been characterized expressing the pluripotency markers and being capable to differentiate to endoderm, mesoderm and ectoderm in vitro., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2019
- Full Text
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31. Establishment of an induced pluripotent stem cell line (FRIMOi005-A) derived from a retinitis pigmentosa patient carrying a dominant mutation in RHO gene.
- Author
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Domingo-Prim J, Riera M, Burés-Jelstrup A, Corcostegui B, and Pomares E
- Subjects
- Adult, Cell Line, Cellular Reprogramming Techniques, Female, Fibroblasts metabolism, Fibroblasts pathology, Humans, Skin metabolism, Skin pathology, Genes, Dominant, Induced Pluripotent Stem Cells metabolism, Induced Pluripotent Stem Cells pathology, Point Mutation, Retinitis Pigmentosa genetics, Retinitis Pigmentosa metabolism, Retinitis Pigmentosa pathology, Sensory Rhodopsins genetics, Sensory Rhodopsins metabolism
- Abstract
Retinitis pigmentosa (RP) is an inherited retinal dystrophy characterized by the progressive degeneration of photoreceptors. In the present study, we have generated an induced pluripotent stem cell (iPSC) line derived from a RP patient with a dominant mutation in the RHO gene, responsible for the synthesis of rhodopsin. The reprogramming of these iPSCs was performed from skin fibroblasts by the Sendai-virus based approach. Characterization of the iPSC line showed a normal karyotype carrying the RHO mutation, expressed pluripotency markers and could be differentiated to endoderm, mesoderm and ectoderm in vitro., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
32. Generation of two iPS cell lines (FRIMOi003-A and FRIMOi004-A) derived from Stargardt patients carrying ABCA4 compound heterozygous mutations.
- Author
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Riera M, Patel A, Burés-Jelstrup A, Corcostegui B, Chang S, Pomares E, Corneo B, and Sparrow JR
- Subjects
- DNA Mutational Analysis, Fibroblasts, Heterozygote, Humans, Karyotype, Mutation, ATP-Binding Cassette Transporters genetics, Cell Line, Induced Pluripotent Stem Cells, Stargardt Disease genetics
- Abstract
Recessive Stargardt disease (STGD1) is an autosomal recessive retinal dystrophy, caused by mutations in the retina-specific ATP-binding cassette transporter (ABCA4) gene, which plays a role as a retinaldehyde flippase in the photoreceptor outer segments. In this work, two human induced pluripotent stem cell (iPSC) lines were generated from STGD1 patients carrying compound heterozygous mutations in ABCA4. Skin fibroblasts were reprogrammed with the Yamanaka factors using a non-integrating, Sendai virus-based approach. Both iPSC lines displayed typical embryonic stem cell morphology, had normal karyotype, expressed several pluripotency markers and were able to differentiate into all three germ layers. Resource table., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
33. Generation of an induced pluripotent stem cell line (FRIMOi002-A) from a retinitis pigmentosa patient carrying compound heterozygous mutations in USH2A gene.
- Author
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Riera M, Patel A, Corcostegui B, Chang S, Corneo B, Sparrow JR, and Pomares E
- Subjects
- Cellular Reprogramming Techniques, Female, Fibroblasts metabolism, Fibroblasts pathology, Humans, Middle Aged, Skin metabolism, Skin pathology, Cell Line, Extracellular Matrix Proteins genetics, Extracellular Matrix Proteins metabolism, Heterozygote, Induced Pluripotent Stem Cells metabolism, Induced Pluripotent Stem Cells pathology, Retinitis Pigmentosa genetics, Retinitis Pigmentosa metabolism, Retinitis Pigmentosa pathology
- Abstract
A human induced pluripotent stem cell (iPSC) line was generated from a female patient affected by autosomal recessive retinitis pigmentosa with two mutations in the USH2A gene: c.2209C > T (p.Arg737Ter) and c.8693A > C (p.Tyr2898Ser). Skin fibroblasts were infected with Sendai virus containing the Yamanaka factors and the resulting cells were fully characterized to confirm successful reprogramming. The iPSC line expressed several pluripotency markers, could generate the three germ layers, had a normal karyotype, carried the two USH2A mutations and was free of Sendai virus. This cell line will serve as a model to unravel the pathogenic mechanisms underlying USH2A-associated retinal degeneration., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
34. Establishment and characterization of an iPSC line (FRIMOi001-A) derived from a retinitis pigmentosa patient carrying PDE6A mutations.
- Author
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Riera M, Patel A, Corcostegui B, Chang S, Sparrow JR, Pomares E, and Corneo B
- Subjects
- Fibroblasts metabolism, Fibroblasts pathology, Humans, Male, Middle Aged, Skin metabolism, Skin pathology, Cell Line, Cyclic Nucleotide Phosphodiesterases, Type 6 genetics, Cyclic Nucleotide Phosphodiesterases, Type 6 metabolism, Eye Proteins genetics, Eye Proteins metabolism, Heterozygote, Induced Pluripotent Stem Cells metabolism, Induced Pluripotent Stem Cells pathology, Mutation, Retinitis Pigmentosa genetics, Retinitis Pigmentosa metabolism, Retinitis Pigmentosa pathology
- Abstract
Retinitis pigmentosa (RP) refers to a clinical and genetic heterogeneous group of inherited retinal degenerations characterized by photoreceptor cell death. In this work, we have generated an induced pluripotent stem cell (iPSC) line derived from a RP patient with two heterozygous mutations in the cGMP-specific phosphodiesterase 6A alpha subunit (PDE6A) gene. Skin fibroblasts were generated and reprogrammed by using a Sendai virus-based approach. The iPSC line had a normal karyotype, carried the two PDE6A mutations, expressed pluripotency markers and could generate endoderm, mesoderm and ectoderm in vitro. Resource table., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
35. Panel-based whole exome sequencing identifies novel mutations in microphthalmia and anophthalmia patients showing complex Mendelian inheritance patterns.
- Author
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Riera M, Wert A, Nieto I, and Pomares E
- Subjects
- Amino Acid Sequence, Animals, Anophthalmos diagnosis, Base Sequence, DNA Mutational Analysis, Heterozygote, Humans, Inheritance Patterns, Microphthalmos diagnosis, Mosaicism, Mutation, Missense, Otx Transcription Factors genetics, PAX6 Transcription Factor genetics, Pedigree, Polymorphism, Single Nucleotide, Retinol-Binding Proteins, Plasma genetics, Sequence Alignment, Exome Sequencing, Anophthalmos genetics, Microphthalmos genetics
- Abstract
Background: Microphthalmia and anophthalmia (MA) are congenital eye abnormalities that show an extremely high clinical and genetic complexity. In this study, we evaluated the implementation of whole exome sequencing (WES) for the genetic analysis of MA patients. This approach was used to investigate three unrelated families in which previous single-gene analyses failed to identify the molecular cause., Methods: A total of 47 genes previously associated with nonsyndromic MA were included in our panel. WES was performed in one affected patient from each family using the AmpliSeq
TM Exome technology and the Ion ProtonTM platform., Results: A novel heterozygous OTX2 missense mutation was identified in a patient showing bilateral anophthalmia who inherited the variant from a parent who was a carrier, but showed no sign of the condition. We also describe a new PAX6 missense variant in an autosomal-dominant pedigree affected by mild bilateral microphthalmia showing high intrafamiliar variability, with germline mosaicism determined to be the most plausible molecular cause of the disease. Finally, a heterozygous missense mutation in RBP4 was found to be responsible in an isolated case of bilateral complex microphthalmia., Conclusion: This study highlights that panel-based WES is a reliable and effective strategy for the genetic diagnosis of MA. Furthermore, using this technique, the mutational spectrum of these diseases was broadened, with novel variants identified in each of the OTX2, PAX6, and RBP4 genes. Moreover, we report new cases of reduced penetrance, mosaicism, and variable phenotypic expressivity associated with MA, further demonstrating the heterogeneity of such disorders., (© 2017 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)- Published
- 2017
- Full Text
- View/download PDF
36. Whole exome sequencing using Ion Proton system enables reliable genetic diagnosis of inherited retinal dystrophies.
- Author
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Riera M, Navarro R, Ruiz-Nogales S, Méndez P, Burés-Jelstrup A, Corcóstegui B, and Pomares E
- Subjects
- Cadherin Related Proteins, Cadherins genetics, Cytoskeletal Proteins, Mutant Proteins genetics, Proteins genetics, Retinal Dystrophies genetics, Retinitis Pigmentosa genetics, c-Mer Tyrosine Kinase genetics, Molecular Diagnostic Techniques methods, Retinal Dystrophies diagnosis, Retinal Dystrophies pathology, Exome Sequencing methods
- Abstract
Inherited retinal dystrophies (IRD) comprise a wide group of clinically and genetically complex diseases that progressively affect the retina. Over recent years, the development of next-generation sequencing (NGS) methods has transformed our ability to diagnose heterogeneous diseases. In this work, we have evaluated the implementation of whole exome sequencing (WES) for the molecular diagnosis of IRD. Using Ion Proton
TM system, we simultaneously analyzed 212 genes that are responsible for more than 25 syndromic and non-syndromic IRD. This approach was used to evaluate 59 unrelated families, with the pathogenic variant(s) successfully identified in 71.18% of cases. Interestingly, the mutation detection rate varied substantially depending on the IRD subtype. Overall, we found 63 different mutations (21 novel) in 29 distinct genes, and performed in vivo functional studies to determine the deleterious impact of variants identified in MERTK, CDH23, and RPGRIP1. In addition, we provide evidences that support CDHR1 as a gene responsible for autosomal recessive retinitis pigmentosa with early macular affectation, and present data regarding the disease mechanism of this gene. Altogether, these results demonstrate that targeted WES of all IRD genes is a reliable, hypothesis-free approach, and a cost- and time-effective strategy for the routine genetic diagnosis of retinal dystrophies., Competing Interests: The authors declare no competing financial interests.- Published
- 2017
- Full Text
- View/download PDF
37. Combined genetic and high-throughput strategies for molecular diagnosis of inherited retinal dystrophies.
- Author
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de Castro-Miró M, Pomares E, Lorés-Motta L, Tonda R, Dopazo J, Marfany G, and Gonzàlez-Duarte R
- Subjects
- DNA Mutational Analysis, Female, Genetic Testing, Genotype, Haplotypes, Humans, Male, Mutation, Pedigree, Polymorphism, Single Nucleotide, Retinal Dystrophies genetics, Spain, Molecular Diagnostic Techniques methods, Retinal Dystrophies diagnosis
- Abstract
Most diagnostic laboratories are confronted with the increasing demand for molecular diagnosis from patients and families and the ever-increasing genetic heterogeneity of visual disorders. Concerning Retinal Dystrophies (RD), almost 200 causative genes have been reported to date, and most families carry private mutations. We aimed to approach RD genetic diagnosis using all the available genetic information to prioritize candidates for mutational screening, and then restrict the number of cases to be analyzed by massive sequencing. We constructed and optimized a comprehensive cosegregation RD-chip based on SNP genotyping and haplotype analysis. The RD-chip allows to genotype 768 selected SNPs (closely linked to 100 RD causative genes) in a single cost-, time-effective step. Full diagnosis was attained in 17/36 Spanish pedigrees, yielding 12 new and 12 previously reported mutations in 9 RD genes. The most frequently mutated genes were USH2A and CRB1. Notably, RD3-up to now only associated to Leber Congenital Amaurosis- was identified as causative of Retinitis Pigmentosa. The main assets of the RD-chip are: i) the robustness of the genetic information that underscores the most probable candidates, ii) the invaluable clues in cases of shared haplotypes, which are indicative of a common founder effect, and iii) the detection of extended haplotypes over closely mapping genes, which substantiates cosegregation, although the assumptions in which the genetic analysis is based could exceptionally lead astray. The combination of the genetic approach with whole exome sequencing (WES) greatly increases the diagnosis efficiency, and revealed novel mutations in USH2A and GUCY2D. Overall, the RD-chip diagnosis efficiency ranges from 16% in dominant, to 80% in consanguineous recessive pedigrees, with an average of 47%, well within the upper range of massive sequencing approaches, highlighting the validity of this time- and cost-effective approach whilst high-throughput methodologies become amenable for routine diagnosis in medium sized labs.
- Published
- 2014
- Full Text
- View/download PDF
38. Union makes strength: a worldwide collaborative genetic and clinical study to provide a comprehensive survey of RD3 mutations and delineate the associated phenotype.
- Author
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Perrault I, Estrada-Cuzcano A, Lopez I, Kohl S, Li S, Testa F, Zekveld-Vroon R, Wang X, Pomares E, Andorf J, Aboussair N, Banfi S, Delphin N, den Hollander AI, Edelson C, Florijn R, Jean-Pierre M, Leowski C, Megarbane A, Villanueva C, Flores B, Munnich A, Ren H, Zobor D, Bergen A, Chen R, Cremers FP, Gonzalez-Duarte R, Koenekoop RK, Simonelli F, Stone E, Wissinger B, Zhang Q, Kaplan J, and Rozet JM
- Subjects
- Adolescent, Adult, Canada, Child, Child, Preschool, China, Cohort Studies, Europe, Female, Humans, Infant, Leber Congenital Amaurosis pathology, Linkage Disequilibrium, Male, Pedigree, Phenotype, Polymorphism, Genetic, Retina metabolism, Retinal Degeneration pathology, United States, Young Adult, Eye Proteins genetics, Leber Congenital Amaurosis genetics, Mutation, Retina pathology, Retinal Degeneration genetics
- Abstract
Leber congenital amaurosis (LCA) is the earliest and most severe retinal degeneration (RD), and the most common cause of incurable blindness diagnosed in children. It is occasionally the presenting symptom of multisystemic ciliopathies which diagnosis will require a specific care of patients. Nineteen LCA genes are currently identified and three of them account for both non-syndromic and syndromic forms of the disease. RD3 (LCA12) was implicated as a LCA gene based on the identification of homozygous truncating mutations in two LCA families despite the screening of large cohorts of patients. Here we provide a comprehensive survey of RD3 mutations and of their clinical expression through the screening of a cohort of 852 patients originating worldwide affected with LCA or early-onset and severe RD. We identified three RD3 mutations in seven unrelated consanguineous LCA families - i.e., a 2 bp deletion and two nonsense mutations - predicted to cause complete loss of function. Five families originating from the Southern Shores of the Mediterranean segregated a similar mutation (c.112C>T, p.R38*) suggesting that this change may have resulted from an ancient founder effect. Considering the low frequency of RD3 carriers, the recurrence risk for LCA in non-consanguineous unions is negligible for both heterozygote and homozygote RD3 individuals. The LCA12 phenotype in our patients is highly similar to those of patients with mutant photoreceptor-specific guanylate cyclase (GUCY2D/LCA1). This observation is consistent with the report of the role of RD3 in trafficking of GUCYs and gives further support to a common mechanism of photoreceptor degeneration in LCA12 and LCA1, i.e., inability to increase cytoplasmic cGMP concentration in outer segments and thus to recover the dark-state. Similar to LCA1, LCA12 patients have no extraocular symptoms despite complete inactivation of both RD3 alleles, supporting the view that extraocular investigations in LCA infants with RD3 mutations should be avoided.
- Published
- 2013
- Full Text
- View/download PDF
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