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3. Constitutional Mutation of PIK3CA : A Variant of Cowden Syndrome?

Author

Vida-Navas, Elena, Barca-Tierno, Verónica, López-Gómez, Victoria, Salazar, María Teresa, Moreno-Pelayo, Miguel A., and Guillén-Ponce, Carmen

Subjects
HEREDITARY cancer syndromes, OVARIAN cancer, THYROID cancer, BREAST cancer, GENETIC mutation, FALLOPIAN tubes, BREAST
Abstract

We present a family in which four individuals have been identified with the same likely pathogenic genetic alteration in the PIK3CA gene at the germinal level; specifically, c.1145G>A p.(Arg382Lys) missense type. The index case patient was diagnosed with multinodular goiter and breast cancer at 61 years old. Among the other three carrier relatives: one has been diagnosed with serous cystadenoma of the ovary and a thyroid nodule with no radiological suspicion of malignancy; the other two present multinodular goiter. Additionally, a sister of three of the carriers suffered from an ovarian teratoma, follicular thyroid carcinoma on multinodular goiter, and high-grade serous ovarian carcinoma. No direct mutation study was performed on her as she had died due to ovarian carcinoma. This finding suggests that the PIK3CA gene should be considered in Cowden-like families when no other gene mutations have been found. Furthermore, this report contributes to characterization of the clinical phenotype caused by mutations in PIK3CA, which may be shared with other hereditary breast and ovarian cancer syndromes. [ABSTRACT FROM AUTHOR]

Published
2024
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4. Novel Cases of Non-Syndromic Hearing Impairment Caused by Pathogenic Variants in Genes Encoding Mitochondrial Aminoacyl-tRNA Synthetases.

Author

Domínguez-Ruiz, María, Olarte, Margarita, Onecha, Esther, García-Vaquero, Irene, Gelvez, Nancy, López, Greizy, Villamar, Manuela, Morín, Matías, Moreno-Pelayo, Miguel A., Morales-Angulo, Carmelo, Polo, Rubén, Tamayo, Martha L., and del Castillo, Ignacio

Subjects
AMINOACYL-tRNA synthetases, HEARING disorders, PROTEIN domains, GENETIC variation, SYMPTOMS
Abstract

Dysfunction of some mitochondrial aminoacyl-tRNA synthetases (encoded by the KARS1, HARS2, LARS2 and NARS2 genes) results in a great variety of phenotypes ranging from non-syndromic hearing impairment (NSHI) to very complex syndromes, with a predominance of neurological signs. The diversity of roles that are played by these moonlighting enzymes and the fact that most pathogenic variants are missense and affect different domains of these proteins in diverse compound heterozygous combinations make it difficult to establish genotype–phenotype correlations. We used a targeted gene-sequencing panel to investigate the presence of pathogenic variants in those four genes in cohorts of 175 Spanish and 18 Colombian familial cases with non-DFNB1 autosomal recessive NSHI. Disease-associated variants were found in five cases. Five mutations were novel as follows: c.766C>T in KARS1, c.475C>T, c.728A>C and c.1012G>A in HARS2, and c.795A>G in LARS2. We provide audiograms from patients at different ages to document the evolution of the hearing loss, which is mostly prelingual and progresses from moderate/severe to profound, the middle frequencies being more severely affected. No additional clinical sign was observed in any affected subject. Our results confirm the involvement of KARS1 in DFNB89 NSHI, for which until now there was limited evidence. [ABSTRACT FROM AUTHOR]

Published
2024
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6. Cingulin regulates hair cell cuticular plate morphology and is required for hearing in human and mouse

Author

Zhu, Guang‐Jie, primary, Huang, Yuhang, additional, Zhang, Linqing, additional, Yan, Keji, additional, Qiu, Cui, additional, He, Yihan, additional, Liu, Qing, additional, Zhu, Chengwen, additional, Morín, Matías, additional, Moreno‐Pelayo, Miguel Ángel, additional, Zhu, Min‐Sheng, additional, Cao, Xin, additional, Zhou, Han, additional, Qian, Xiaoyun, additional, Xu, Zhigang, additional, Chen, Jie, additional, Gao, Xia, additional, and Wan, Guoqiang, additional

Published
2023
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8. Genetic Evaluation of Prelingual Hearing Impairment: Recommendations of an European Network for Genetic Hearing Impairment

Author

Jonard, Laurence, primary, Brotto, Davide, additional, Moreno-Pelayo, Miguel A., additional, del Castillo, Ignacio, additional, Kremer, Hannie, additional, Pennings, Ronald, additional, Caria, Helena, additional, Fialho, Graça, additional, Boudewyns, An, additional, Van Camp, Guy, additional, Ołdak, Monika, additional, Oziębło, Dominika, additional, Deggouj, Naïma, additional, De Siati, Romolo Daniele, additional, Gasparini, Paolo, additional, Girotto, Giorgia, additional, Verstreken, Margriet, additional, Dossena, Silvia, additional, Roesch, Sebastian, additional, Battelino, Saba, additional, Trebušak Podkrajšek, Katarina, additional, Warnecke, Athanasia, additional, Lenarz, Thomas, additional, Lesinski-Schiedat, Anke, additional, Mondain, Michel, additional, Roux, Anne-Françoise, additional, Denoyelle, Françoise, additional, Loundon, Natalie, additional, Serey Gaut, Margaux, additional, Trevisi, Patrizia, additional, Rubinato, Elisa, additional, Martini, Alessandro, additional, and Marlin, Sandrine, additional

Published
2023
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9. Specific correction of pyruvate kinase deficiency-causing point mutations by CRISPR/Cas9 and single-stranded oligodeoxynucleotides

Author

Fañanas-Baquero, Sara, primary, Morín, Matías, additional, Fernández, Sergio, additional, Ojeda-Perez, Isabel, additional, Dessy-Rodriguez, Mercedes, additional, Giurgiu, Miruna, additional, Bueren, Juan A., additional, Moreno-Pelayo, Miguel Angel, additional, Segovia, Jose Carlos, additional, and Quintana-Bustamante, Oscar, additional

Published
2023
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10. Search for new genes, molecular mechanisms and diagnostic tools in postlingual hereditary hearing loss

Author

Moreno Pelayo, Miguel Ángel, Morín Rodríguez, Matías, Steel, Karen, Lachgar Ruiz, María, Moreno Pelayo, Miguel Ángel, Morín Rodríguez, Matías, Steel, Karen, and Lachgar Ruiz, María

Abstract

Las hipoacusias neurosensoriales no sindrómicas son el trastorno sensorial más común y presentan una alta heterogeneidad genética. La identificación de nuevos genes y variantes asociados a hipoacusia avanza a un ritmo muy rápido, lo que hace que el uso de herramientas de secuenciación masiva sea esencial para realizar un diagnóstico genético. En este trabajo, hemos utilizado OTO-NGS-panel V2, un panel de secuenciación masiva diseñado por nuestro grupo que contiene 117 genes asociados a hipoacusias para estudiar el espectro mutacional de las hipoacusias no sindrómicas de herencia autosómica dominante en la población española. OTO-NGS-panel V2 fue validado para la identificación de mutaciones puntuales, pequeñas inserciones y deleciones y variaciones del número de copias. Con esta herramienta, se analizaron 108 familias con hipoacusia no sindrómica e identificamos la variante causal en 39 casos, lo que constituye una tasa diagnóstica del 36,11%. Los genes con mayor prevalencia son WFS1 (7,41 %), seguido de MYO7A (5,56 %), MYO6 (4,63 %), TECTA (2,78 %) y ACTG1 (2,78 %). Para determinar la causa genética de la sordera en los casos que permanecieron sin diagnosticar tras el análisis con OTO-NGS-panel V2, diseñamos un panel de genes candidatos, que incluye genes asociados a sordera en ratón pero sin mutaciones reportadas en humanos hasta la fecha. Se identificaron variantes candidatas en los genes XIRP2, USP31, PLS1 y KCNK5..., Non-syndromic sensorineural hearing loss (SNHL) is the most common sensory disorder, and it presents a high genetic heterogeneity. New genes and variants associated with hearing loss are described at a very rapid pace, making the use of next-generation sequencing (NGS) approaches essential to undertake a genetic diagnosis.We have used OTO-NGS-panel V2, a custom-designed NGS panel containing 117 genes associated with hearing loss to study the mutational spectrum of autosomal dominant non-syndromic hearing loss in the Spanish clinical population. OTO-NGS-panel V2 was validated for the identification of single nucleotide variants (SNVs), small insertions and deletions (Indels) and copy number variations (CNVs), and 108 Spanish families with autosomal dominant non-syndromic hearing loss (ADNSHL) were analysed. We identified the causative variant in 39 cases, constituting a diagnostic rate of 36.11%. The genes with the highest prevalence are WFS1 (7.41%) followed by MYO7A (5.56%), MYO6 (4.63%), TECTA (2.78%) and ACTG1 (2.78%). To identify the genetic cause of deafness in the cases that remained undiagnosed upon analysis with OTO-NGS-panel V2, we designed a candidate gene panel, including genes known to cause deafness in mice but with no human mutations reported so far. Candidate variants were found in the genes XIRP2, USP31, PLS1 and KCNK5...

Published
2023

11. Pathogenic variants of the coenzyme A biosynthesis-associated enzyme phosphopantothenoylcysteine decarboxylase cause autosomal-recessive dilated cardiomyopathy

Author

Instituto de Salud Carlos III, European Commission, Ministerio de Economía, Industria y Competitividad (España), Comunidad de Madrid, Ramón-Maiques, Santiago [0000-0001-9674-8088], Bravo-Alonso, Irene, Morin, Matias, Arribas-Carreira, Laura, Álvarez, Mar, Padrón-Giner, Consuelo, Soletto, Lucia, Santolaria, Carlos, Ramón-Maiques, Santiago, Ugarte, Magdalena, Rodríguez-Pombo, Pilar, Ariño, Joaquín, Moreno-Pelayo, Miguel Ángel, Pérez, Belén, Instituto de Salud Carlos III, European Commission, Ministerio de Economía, Industria y Competitividad (España), Comunidad de Madrid, Ramón-Maiques, Santiago [0000-0001-9674-8088], Bravo-Alonso, Irene, Morin, Matias, Arribas-Carreira, Laura, Álvarez, Mar, Padrón-Giner, Consuelo, Soletto, Lucia, Santolaria, Carlos, Ramón-Maiques, Santiago, Ugarte, Magdalena, Rodríguez-Pombo, Pilar, Ariño, Joaquín, Moreno-Pelayo, Miguel Ángel, and Pérez, Belén

Abstract

Coenzyme A (CoA) is an essential cofactor involved in a range of metabolic pathways including the activation of long-chain fatty acids for catabolism. Cells synthesize CoA de novo from vitamin B5 (pantothenate) via a pathway strongly conserved across prokaryotes and eukaryotes. In humans, it involves five enzymatic steps catalyzed by four enzymes: pantothenate kinase (PANK [isoforms 1-4]), 4'-phosphopantothenoylcysteine synthetase (PPCS), phosphopantothenoylcysteine decarboxylase (PPCDC), and CoA synthase (COASY). To date, inborn errors of metabolism associated with all of these genes, except PPCDC, have been described, two related to neurodegeneration with brain iron accumulation (NBIA), and one associated with a cardiac phenotype. This paper reports another defect in this pathway (detected in two sisters), associated with a fatal cardiac phenotype, caused by biallelic variants (p.Thr53Pro and p.Ala95Val) of PPCDC. PPCDC enzyme (EC 4.1.1.36) catalyzes the decarboxylation of 4'-phosphopantothenoylcysteine to 4'-phosphopantetheine in CoA biosynthesis. The variants p.Thr53Pro and p.Ala95Val affect residues highly conserved across different species; p.Thr53Pro is involved in the binding of flavin mononucleotide, and p.Ala95Val is likely a destabilizing mutation. Patient-derived fibroblasts showed an absence of PPCDC protein, and nearly 50% reductions in CoA levels. The cells showed clear energy deficiency problems, with defects in mitochondrial respiration, and mostly glycolytic ATP synthesis. Functional studies performed in yeast suggest these mutations to be functionally relevant. In summary, this work describes a new, ultra-rare, severe inborn error of metabolism due to pathogenic variants of PPCDC.

Published
2023

12. Evolution of CRISPR-associated endonucleases as inferred from resurrected proteins

Author

Universidad de Alicante. Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante. Instituto Multidisciplinar para el Estudio del Medio "Ramón Margalef", Alonso-Lerma, Borja, Jabalera, Ylenia, Samperio, Sara, Morin, Matias, Fernandez, Almudena, Hille, Logan T., Silverstein, Rachel A., Quesada-Ganuza, Ane, Reifs, Antonio, Fernández-Peñalver, Sergio, Benitez, Yolanda, Soletto, Lucia, Gavira, Jose A., Diaz, Adrian, Vranken, Wim, Sanchez-Mejias, Avencia, Güell, Marc, Mojica, Francisco J.M., Kleinstiver, Benjamin P., Moreno-Pelayo, Miguel A., Montoliu, Lluis, Perez-Jimenez, Raul, Universidad de Alicante. Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante. Instituto Multidisciplinar para el Estudio del Medio "Ramón Margalef", Alonso-Lerma, Borja, Jabalera, Ylenia, Samperio, Sara, Morin, Matias, Fernandez, Almudena, Hille, Logan T., Silverstein, Rachel A., Quesada-Ganuza, Ane, Reifs, Antonio, Fernández-Peñalver, Sergio, Benitez, Yolanda, Soletto, Lucia, Gavira, Jose A., Diaz, Adrian, Vranken, Wim, Sanchez-Mejias, Avencia, Güell, Marc, Mojica, Francisco J.M., Kleinstiver, Benjamin P., Moreno-Pelayo, Miguel A., Montoliu, Lluis, and Perez-Jimenez, Raul

Abstract

Clustered regularly interspaced short palindromic repeats (CRISPR)-associated Cas9 is an effector protein that targets invading DNA and plays a major role in the prokaryotic adaptive immune system. Although Streptococcus pyogenes CRISPR–Cas9 has been widely studied and repurposed for applications including genome editing, its origin and evolution are poorly understood. Here, we investigate the evolution of Cas9 from resurrected ancient nucleases (anCas) in extinct firmicutes species that last lived 2.6 billion years before the present. We demonstrate that these ancient forms were much more flexible in their guide RNA and protospacer-adjacent motif requirements compared with modern-day Cas9 enzymes. Furthermore, anCas portrays a gradual palaeoenzymatic adaptation from nickase to double-strand break activity, exhibits high levels of activity with both single-stranded DNA and single-stranded RNA targets and is capable of editing activity in human cells. Prediction and characterization of anCas with a resurrected protein approach uncovers an evolutionary trajectory leading to functionally flexible ancient enzymes.

Published
2023

14. Novel Pathogenic Variants in the Gene Encoding Stereocilin (STRC) Causing Non-Syndromic Moderate Hearing Loss in Spanish and Argentinean Subjects.

Author

Domínguez-Ruiz, María, Ruiz-Palmero, Laura, Buonfiglio, Paula I., García-Vaquero, Irene, Gómez-Rosas, Elena, Goñi, Marina, Villamar, Manuela, Morín, Matías, Moreno-Pelayo, Miguel A., Elgoyhen, Ana B., del Castillo, Francisco J., Dalamón, Viviana, and del Castillo, Ignacio

Subjects
GENETIC variation, HEARING disorders, GENETIC epidemiology, DNA sequencing, GENETIC mutation
Abstract

Non-syndromic hearing impairment (NSHI) is a very heterogeneous genetic condition, involving over 130 genes. Mutations in GJB2, encoding connexin-26, are a major cause of NSHI (the DFNB1 type), but few other genes have significant epidemiological contributions. Mutations in the STRC gene result in the DFNB16 type of autosomal recessive NSHI, a common cause of moderate hearing loss. STRC is located in a tandem duplicated region that includes the STRCP1 pseudogene, and so it is prone to rearrangements causing structural variations. Firstly, we screened a cohort of 122 Spanish familial cases of non-DFNB1 NSHI with at least two affected siblings and unaffected parents, and with different degrees of hearing loss (mild to profound). Secondly, we screened a cohort of 64 Spanish sporadic non-DFNB1 cases, and a cohort of 35 Argentinean non-DFNB1 cases, all of them with moderate hearing loss. Amplification of marker D15S784, massively parallel DNA sequencing, multiplex ligation-dependent probe amplification and long-range gene-specific PCR followed by Sanger sequencing were used to search and confirm single-nucleotide variants (SNVs) and deletions involving STRC. Causative variants were found in 13 Spanish familial cases (10.7%), 5 Spanish simplex cases (7.8%) and 2 Argentinean cases (5.7%). In all, 34 deleted alleles and 6 SNVs, 5 of which are novel. All affected subjects had moderate hearing impairment. Our results further support this strong genotype–phenotype correlation and highlight the significant contribution of STRC mutations to moderate NSHI in the Spanish population. [ABSTRACT FROM AUTHOR]

Published
2023
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15. Selective miRNA inhibition in CD8+ cytotoxic T lymphocytes enhances HIV-1 specific cytotoxic responses

Author

Madrid-Elena, Nadia, primary, Serrano-Villar, Sergio, additional, Gutiérrez, Carolina, additional, Sastre, Beatriz, additional, Morín, Matías, additional, Luna, Laura, additional, Martín, Laura, additional, Santoyo-López, Javier, additional, López-Huertas, María Rosa, additional, Moreno, Elena, additional, García-Bermejo, María Laura, additional, Moreno-Pelayo, Miguel Ángel, additional, and Moreno, Santiago, additional

Published
2022
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16. Novel Pathogenic Variants in PJVK, the Gene Encoding Pejvakin, in Subjects with Autosomal Recessive Non-Syndromic Hearing Impairment and Auditory Neuropathy Spectrum Disorder

Author

Domínguez-Ruiz, María, Rodríguez-Ballesteros, Montserrat, Gandía, Marta, Gómez-Rosas, Elena, Villamar, Manuela, Scimemi, Pietro, Mancini, Patrizia, Rendtorff, Nanna D., Moreno-Pelayo, Miguel A., Tranebjaerg, Lisbeth, Medà, Carme, Santarelli, Rosamaria, Del Castillo, Ignacio, Domínguez-Ruiz, María, Rodríguez-Ballesteros, Montserrat, Gandía, Marta, Gómez-Rosas, Elena, Villamar, Manuela, Scimemi, Pietro, Mancini, Patrizia, Rendtorff, Nanna D., Moreno-Pelayo, Miguel A., Tranebjaerg, Lisbeth, Medà, Carme, Santarelli, Rosamaria, and Del Castillo, Ignacio

Abstract

Pathogenic variants in the PJVK gene cause the DFNB59 type of autosomal recessive non-syndromic hearing impairment (AR-NSHI). Phenotypes are not homogeneous, as a few subjects show auditory neuropathy spectrum disorder (ANSD), while others show cochlear hearing loss. The numbers of reported cases and pathogenic variants are still small to establish accurate genotype-phenotype correlations. We investigated a cohort of 77 Spanish familial cases of AR-NSHI, in whom DFNB1 had been excluded, and a cohort of 84 simplex cases with isolated ANSD in whom OTOF variants had been excluded. All seven exons and exon-intron boundaries of the PJVK gene were sequenced. We report three novel DFNB59 cases, one from the AR-NSHI cohort and two from the ANSD cohort, with stable, severe to profound NSHI. Two of the subjects received unilateral cochlear implantation, with apparent good outcomes. Our study expands the spectrum of PJVK mutations, as we report four novel pathogenic variants: p.Leu224Arg, p.His294Ilefs*43, p.His294Asp and p.Phe317Serfs*20. We review the reported cases of DFNB59, summarize the clinical features of this rare subtype of AR-NSHI and discuss the involvement of PJVK in ANSD.

Published
2022

17. CRISPR/Cas9-Mediated Allele-Specific Disruption of a Dominant COL6A1 Pathogenic Variant Improves Collagen VI Network in Patient Fibroblasts

Author

López-Márquez, Arístides, primary, Morín, Matías, additional, Fernández-Peñalver, Sergio, additional, Badosa, Carmen, additional, Hernández-Delgado, Alejandro, additional, Natera-de Benito, Daniel, additional, Ortez, Carlos, additional, Nascimento, Andrés, additional, Grinberg, Daniel, additional, Balcells, Susanna, additional, Roldán, Mónica, additional, Moreno-Pelayo, Miguel Ángel, additional, and Jiménez-Mallebrera, Cecilia, additional

Published
2022
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18. Novel Pathogenic Variants in PJVK, the Gene Encoding Pejvakin, in Subjects with Autosomal Recessive Non-Syndromic Hearing Impairment and Auditory Neuropathy Spectrum Disorder

Author

Domínguez-Ruiz, María, primary, Rodríguez-Ballesteros, Montserrat, additional, Gandía, Marta, additional, Gómez-Rosas, Elena, additional, Villamar, Manuela, additional, Scimemi, Pietro, additional, Mancini, Patrizia, additional, Rendtorff, Nanna D., additional, Moreno-Pelayo, Miguel A., additional, Tranebjaerg, Lisbeth, additional, Medà, Carme, additional, Santarelli, Rosamaria, additional, and del Castillo, Ignacio, additional

Published
2022
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19. Therapeutic Potential of EWSR1–FLI1 Inactivation by CRISPR/Cas9 in Ewing Sarcoma

Author

Cervera, Saint T., primary, Rodríguez-Martín, Carlos, additional, Fernández-Tabanera, Enrique, additional, Melero-Fernández de Mera, Raquel M., additional, Morin, Matias, additional, Fernández-Peñalver, Sergio, additional, Iranzo-Martínez, Maria, additional, Amhih-Cardenas, Jorge, additional, García-García, Laura, additional, González-González, Laura, additional, Moreno-Pelayo, Miguel Angel, additional, and Alonso, Javier, additional

Published
2021
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20. CSVS, a crowdsourcing database of the Spanish population genetic variability

Author

Ministerio de Economía y Competitividad (España), Centro de Investigación Biomédica en Red Enfermedades Raras (España), Comunidad de Madrid, European Commission, Universidad Autónoma de Madrid, Fundación Ramón Areces, Peña-Chilet, María, Roldán, Gema, Pérez-Florido, Javier, Ortuño, Francisco M., Carmona, Rosario, Aquino, Virginia, López-López, Daniel, Loucera, Carlos, Fernández-Rueda, José L., Gallego, Asunción, García-García, Francisco, González-Neira, Anna, Pita, Guillermo, Núñez-Torres, Rocío, Santoyo-López, Javier, Ayuso, Carmen, Mínguez, Pablo, Ávila-Fernández, Almudena, Cortón, Marta, Moreno-Pelayo, Miguel Ángel, Morin, Matías, Gallego-Martinez, Álvaro, López-Escamez, José A., Borrego, Salud, Antiñolo, Guillermo, Amigo, Jorge, Salgado-Garrido, Josefa, Pasalodos-Sánchez, Sara, Morte, Beatriz, Spanish Exome Crowdsourcing Consortium, Carracedo, Ángel, Alonso, Ángel, Dopazo, Joaquín, Ministerio de Economía y Competitividad (España), Centro de Investigación Biomédica en Red Enfermedades Raras (España), Comunidad de Madrid, European Commission, Universidad Autónoma de Madrid, Fundación Ramón Areces, Peña-Chilet, María, Roldán, Gema, Pérez-Florido, Javier, Ortuño, Francisco M., Carmona, Rosario, Aquino, Virginia, López-López, Daniel, Loucera, Carlos, Fernández-Rueda, José L., Gallego, Asunción, García-García, Francisco, González-Neira, Anna, Pita, Guillermo, Núñez-Torres, Rocío, Santoyo-López, Javier, Ayuso, Carmen, Mínguez, Pablo, Ávila-Fernández, Almudena, Cortón, Marta, Moreno-Pelayo, Miguel Ángel, Morin, Matías, Gallego-Martinez, Álvaro, López-Escamez, José A., Borrego, Salud, Antiñolo, Guillermo, Amigo, Jorge, Salgado-Garrido, Josefa, Pasalodos-Sánchez, Sara, Morte, Beatriz, Spanish Exome Crowdsourcing Consortium, Carracedo, Ángel, Alonso, Ángel, and Dopazo, Joaquín

Abstract

The knowledge of the genetic variability of the local population is of utmost importance in personalized medicine and has been revealed as a critical factor for the discovery of new disease variants. Here, we present the Collaborative Spanish Variability Server (CSVS), which currently contains more than 2000 genomes and exomes of unrelated Spanish individuals. This database has been generated in a collaborative crowdsourcing effort collecting sequencing data produced by local genomic projects and for other purposes. Sequences have been grouped by ICD10 upper categories. A web interface allows querying the database removing one or more ICD10 categories. In this way, aggregated counts of allele frequencies of the pseudo-control Spanish population can be obtained for diseases belonging to the category removed. Interestingly, in addition to pseudo-control studies, some population studies can be made, as, for example, prevalence of pharmacogenomic variants, etc. In addition, this genomic data has been used to define the first Spanish Genome Reference Panel (SGRP1.0) for imputation. This is the first local repository of variability entirely produced by a crowdsourcing effort and constitutes an example for future initiatives to characterize local variability worldwide. CSVS is also part of the GA4GH Beacon network. CSVS can be accessed at: http://csvs.babelomics.org/.

Published
2021

21. A leaky mutation in CD3D differentially affects αβ and γδ T cells and leads to a Tαβ-Tγδ+B+NK+ human SCID

Author

Gil, Juana, Busto, Elena M., Garcillan, Beatriz, Chean, Carmen, Garcia-Rodriguez, Maria Cruz, Diaz-Alderete, Andrea, Navarro, Joaquin, Reine, Jesus, Mencia, Angeles, Gurbindo, Dolores, Belendez, Cristina, Gordillo, Isabel, Duchniewicz, Marlena, Hohne, Kerstin, Garcia-Sanchez, Felix, Fernandez-Cruz, Eduardo, Lopez-Granados, Eduardo, Schamel, Wolfgang W.A., Moreno-Pelayo, Miguel A., Recio, Maria J., and Regueiro, Jose R.

Subjects
T cells -- Receptors -- Physiological aspects -- Genetic aspects -- Research, Antigen receptors, T cell -- Physiological aspects -- Research, Mutation (Biology) -- Health aspects -- Research, Severe combined immunodeficiency -- Risk factors -- Genetic aspects -- Research, Health care industry
Abstract

T cells recognize antigens via their cell surface TCR and are classified as either αβ or γδ depending on the variable chains in their TCR, α and βor γ and δ, respectively. Both αβ and γδ TCRs also contain several invariant chains, including CD3δ, which support surface TCR expression and transduce the TCR signal. Mutations in variable chains would be expected to affect a single T cell lineage, while mutations in the invariant chains would affect all T cells. Consistent with this, all CD3δ-deficient patients described to date showed a complete block in T cell development. However, CD3δ-KO mice have an αβ T cell-specific defect. Here, we report 2 unrelated cases of SCID with a selective block in αβ but not in γδ Tcell development, associated with a new splicing mutation in the CD3D gene. The patients' T cells showed reduced CD3D transcripts, CD3δ proteins, surface TCR, and early TCR signaling. Their lymph nodes showed severe T cell depletion, recent thymus emigrants in peripheral blood were strongly decreased, and the scant αβ T cells were oligoclonal. T cell-dependent B cell functions were also impaired, despite the presence of normal B cell numbers. Strikingly, despite the specific loss of αβ T cells, surface TCR expression was more reduced in γδ than in αβ T cells. Analysis of individuals with this CD3D mutation thus demonstrates the contrasting CD3δ requirements for αβ versus γδ Tcell development and TCR expression in humans and highlights the diagnostic and clinical relevance of studying both TCR isotypes when a T cell defect is suspected., Introduction T lymphocytes recognize antigens by means of a cell surface complex termed the TCR. The TCR contains 2 variable chains to bind antigens and several invariant chains to support [...]

Published
2011
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26. CSVS, a crowdsourcing database of the Spanish population genetic variability

Author

Peña-Chilet, María, Roldán Gema, Perez-Florido, Javier, Ortuño, Francisco M., Carmona, Rosario, Aquino, Virginia, Lopez-Lopez, Daniel, Loucera, Carlos, Fernandez-Rueda, Jose L., Gallego, Asunción, García-García, Francisco, González-Neira, Anna, Pita, Guillermo, Núñez-Torres, Rocío, Santoyo-López, Javier, Ayuso, Carmen, Minguez, Pablo, Avila-Fernandez, Almudena, Corton, Marta, Moreno-Pelayo, Miguel Ángel, Morin, Matías, Gallego-Martinez, Alvaro, Lopez-Escamez, Jose A., Borrego, Salud, Antiñolo, Guillermo, Amigo, Jorge, Salgado-Garrido, Josefa, Pasalodos-Sanchez, Sara, Morte, Beatriz, The Spanish Exome Crowdsourcing Consortium, Carracedo Álvarez, Ángel, Alonso, Ángel, Dopazo, Joaquín, Grinberg Vaisman, Daniel Raúl, [Peña-Chilet,M, Roldán,G, Perez-Florido,J, Ortuño,FM, Carmona,R, Aquino,V, Lopez-Lopez,D, Loucera,C, Fernandez-Rueda,JL, Dopazo,J] Clinical Bioinformatics Area, Fundacion Progreso y Salud (FPS), Hospital Virgen del Rocío, Sevilla, Spain. [Peña-Chilet,M, Dopazo,J] Bioinformatics in Rare Diseases (BiER), Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Sevilla, Spain. [Peña-Chilet,M, Dopazo,J] Computational Systems Medicine group, Institute of Biomedicine of Seville (IBIS) Hospital Virgen del Rocío, Sevilla, Spain. [Perez-Florido,J, Dopazo,J] Functional Genomics Node, FPS/ELIXIR-ES, Hospital Virgen del Rocío, Sevilla, Spain. [Gallego,A] Sistemas Genomicos, Paterna, Valencia, Spain. [García-Garcia,F] Unidad de Bioinformatica y Bioestadística, Centro de Investigacion Príncipe Felipe (CIPF), Valencia, Spain. [González-Neira,A, Pita,G, Núñez-Torres,R] Human Genotyping Unit–Centro Nacional de Genotipado (CEGEN), Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. [Santoyo-López,J] Edinburgh Genomics, The University of Edinburgh, Edinburgh, UK. [Ayuso,C, Minguez,P, Avila-Fernandez,A, Corton,M] Department of Genetics, Instituto de Investigacion Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autonoma de Madrid (IIS-FJD, UAM), Madrid, Spain. [Minguez,P] Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain. [Moreno-Pelayo,MÁ, Morin,M] Servicio de Genetica, Ramón y Cajal Institute of Health Research (IRYCIS) and Biomedical Network Research Centre on Rare Diseases (CIBERER), Madrid, Spain, [Gallego-Martinez,A, Lopez-Escamez,JA] Otology & Neurotology Group CTS 495, Department of Genomic Medicine, Centre for Genomics and Oncological Research (GENYO), Pfizer University of Granada, Granada, Spain. [Gallego-Martinez,A, Lopez-Escamez,JA] Department of Otolaryngology, Instituto de Investigacion Biosanitaria, IBS. GRANADA, Hospital Universitario Virgen de las Nieves, Universidad de Granada, Granada, Spain. [Borrego,S, Antiñolo,G] Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío /CSIC/University of Seville, Seville, Spain. [Borrego,S, Antiñolo,G] Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain. [Amigo,J, Carracedo,Á] Fundacion Pública Galega de Medicina Xenómica, SERGAS, IDIS, Santiago de Compostela, Spain. [Salgado-Garrido,J, Pasalodos-Sanchez,S, Alonso,Á] Navarrabiomed-IdiSNA, Complejo Hospitalario de Navarra, Universidad Publica de Navarra (UPNA), IdiSNA (Navarra Institute for Health Research), Pamplona, Navarra, Spain. [Morte,B] Undiagnosed Rare Diseases Programme (ENoD). Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain. [Carracedo,Á] Grupo de Medicina Xenomica, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), CIMUS, Universidade de Santiago de Compostela, Santiago de Compostela, España., Spanish Ministry of Economy and Competitiveness [SAF2017-88908-R, PT17/0009/0006 to J.D., PI19/00321 and CIBERER ACCI-06/07/0036 to C.A., PI14-948, PI17-1659 and CIBERER ACCI-06/07/0036 to M.A.M.P.], Regional Government of Madrid, RAREGenomics CM [B2017/BMD-3721 to C.A. and B2017/BMD3721 to M.A.M.P.], all co-funded with European Regional Development Funds (ERDF) as well as EU H2020-INFRADEV-1-2015-1 ELIXIR-EXCELERATE [676559], University Chair UAM-IIS-FJD of Genomic Medicine and the Ramon Areces Foundation also supported this work. Funding for open access charge: Spanish Ministry of Economy and Competitiveness [SAF2017-88908-R]., Ministerio de Economía, Industria y Competitividad (España), Comunidad de Madrid, European Commission, Fundación Ramón Areces, Ministerio de Economía y Competitividad (España), Centro de Investigación Biomédica en Red Enfermedades Raras (España), and Universidad Autónoma de Madrid

Subjects
Genetics, population, Població, AcademicSubjects/SCI00010, computer.software_genre, Bases de dades, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], 0302 clinical medicine, Gene Frequency, Genética de poblaciones, Databases, Genetic, Database Issue, Exome, Precision Medicine, 0303 health sciences, education.field_of_study, Database, Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics::Genetics, Population [Medical Subject Headings], Chromosome Mapping, Genomics, Bases de datos genéticas, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome, Human [Medical Subject Headings], 3. Good health, Databases, genetic, Information Science::Information Science::Data Collection::Crowdsourcing [Medical Subject Headings], Crowdsourcing, Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics::Genomics [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Chromosome Mapping::Physical Chromosome Mapping [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Variation [Medical Subject Headings], Participación colectiva, Population, Proveïment participatiu, Biology, Variación genética, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Exome [Medical Subject Headings], Genètica de poblacions humanes, 03 medical and health sciences, Databases, Information Science::Information Science::Information Storage and Retrieval::Databases as Topic::Databases, Factual::Databases, Genetic [Medical Subject Headings], Genetic variation, Genetics, Humans, Genetic variability, Espanya, education, Allele frequency, Alleles, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Alleles [Medical Subject Headings], 030304 developmental biology, Geographical Locations::Geographic Locations::Europe::Spain [Medical Subject Headings], Internet, Genoma humà -- Espanya, business.industry, Genome, Human, Genetic Variation, Human population genetics, Gene frequency, Frecuencia génica, Genetics, Population, Spain, Personalized medicine, business, Phenomena and Processes::Genetic Phenomena::Gene Frequency [Medical Subject Headings], computer, 030217 neurology & neurosurgery, Imputation (genetics), Software
Abstract

The knowledge of the genetic variability of the local population is of utmost importance in personalized medicine and has been revealed as a critical factor for the discovery of new disease variants. Here, we present the Collaborative Spanish Variability Server (CSVS), which currently contains more than 2000 genomes and exomes of unrelated Spanish individuals. This database has been generated in a collaborative crowdsourcing effort collecting sequencing data produced by local genomic projects and for other purposes. Sequences have been grouped by ICD10 upper categories. A web interface allows querying the database removing one or more ICD10 categories. In this way, aggregated counts of allele frequencies of the pseudo-control Spanish population can be obtained for diseases belonging to the category removed. Interestingly, in addition to pseudo-control studies, some population studies can be made, as, for example, prevalence of pharmacogenomic variants, etc. In addition, this genomic data has been used to define the first Spanish Genome Reference Panel (SGRP1.0) for imputation. This is the first local repository of variability entirely produced by a crowdsourcing effort and constitutes an example for future initiatives to characterize local variabilityworldwide. CSVS is also part of the GA4GH Beacon network., Spanish Ministry of Economy and Competitiveness SAF2017-88908-R PT17/0009/0006 PI19/00321 CIBERER ACCI-06/07/0036 PI14-948 PI171659, Regional Government of Madrid, RAREGenomicsCM B2017/BMD3721 B2017/BMD-3721, European Union (EU), European Union (EU) 676559, University Chair UAM-IIS-FJD of Genomic Medicine, Ramon Areces Foundation

Published
2020

27. A mutation in CCDC50, a gene encoding an effector of epidermal growth factor-mediated cell signaling, causes progressive hearing loss

Author

Modamio-Hoybjor, Silvia, Mencia, Angeles, Goodyear, Richard, Del Castillo, Ignacio, Richardson, Guy, Moreno, Felipe, and Moreno-Pelayo, Miguel Angel

Subjects
Hearing loss -- Genetic aspects, Hearing loss -- Research, Epidermal growth factor -- Research, Cellular signal transduction -- Research, Biological sciences
Abstract

The identification of a mutation in CCDC50 is described as the cause if hearing loss in the family by examining its expression pattern in mouse inner ear. CCDC50 encodes Ymer an effector of epidermal growth factor (EGF)-mediated cell signaling expressed in different organs.

Published
2007

28. Simple Protocol for Generating and Genotyping Genome-Edited Mice With CRISPR-Cas9 Reagents

Author

Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Fundación Ramón Areces, Comunidad de Madrid, Centro de Investigación Biomédica en Red Cáncer (España), Fernández, Almudena, Morin, Matias, Muñoz‐Santos, Diego, Josa, Santiago, Montero, Andrea, Rubio‐Fernández, Marcos, Cantero, Marta, Fernández, Julia, Hierro, María Jesús del, Castrillo, Marta, Moreno‐Pelayo, Miguel Ángel, Montoliu, Lluís, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Fundación Ramón Areces, Comunidad de Madrid, Centro de Investigación Biomédica en Red Cáncer (España), Fernández, Almudena, Morin, Matias, Muñoz‐Santos, Diego, Josa, Santiago, Montero, Andrea, Rubio‐Fernández, Marcos, Cantero, Marta, Fernández, Julia, Hierro, María Jesús del, Castrillo, Marta, Moreno‐Pelayo, Miguel Ángel, and Montoliu, Lluís

Abstract

The simple protocol described in this article aims to provide all required information, as a comprehensive, easy‐to‐follow step‐by‐step method, to ensure the generation of the expected genome‐edited mice. Here, we provide protocols for the preparation of CRISPR‐Cas9 reagents for microinjection and electroporation into one‐cell mouse embryos to create knockout or knock‐in mouse models, and for genotyping the resulting offspring with the latest innovative next‐generation sequencing methods.

Published
2020

30. Prevalence and evolutionary origins of the del(GJB6-D13S1830) mutation in the DFNB1 locus in hearing-impaired subjects: a multicenter study

Author

del Castillo, Ignacio, Moreno-Pelayo, Miguel A., del Castillo, Francisco J., Brownstein, Zippora, Marlin, Sandrine, Adina, Quint, Cockburn, David J., Pandya, Arti, Siemering, Kirby R., Chamberlin, G. Parker, Ballana, Ester, Wuyts, Wim, Maciel-Guerra, Andrea Trevas, Alvarez, Araceli, Villamar, Manuela, Shohat, Mordechai, Abeliovich, Dvorah, Dahl, Hans-Henrik M., Estivill, Xavier, Gasparini, Paolo, Hutchin, Tim, Nance, Walter E., Sartorato, Edi L., Smith, Richard J.H., Van Camp, Guy, Avraham, Karen B., Petit, Christine, and Moreno, Felipe

Subjects
Human genetics -- Research, Biological sciences
Published
2003

31. MOESM1 of Perrault syndrome with neurological features in a compound heterozygote for two TWNK mutations: overlap of TWNK-related recessive disorders

Author

Domínguez-Ruiz, María, García-Martínez, Alberto, Corral-Juan, Marc, Pérez-Álvarez, Ángel, Plasencia, Ana, Villamar, Manuela, Moreno-Pelayo, Miguel, Matilla-Dueñas, Antoni, Menéndez-González, Manuel, and Castillo, Ignacio

Abstract

Additional file 1: Table S1. Relevant mutations obtained by whole-exome sequencing of subject II: 3.

Published
2019
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32. Generacion y caracterizacion de nuevos modelos celulares asociados al deficit neural en IGF-1

Author

Rodriguez-de la Rosa, Lourdes, García-Mato, Ángela, Vandenbroucke, Roosmarijn, Morin, Matias, Moreno-Pelayo, Miguel Angel, Montoliu, Lluís, Varela-Nieto, Isabel, and Asociación Española Contra el Cáncer

Abstract

Resumen del póster presentado al 42nd Congress of the Spanish Society of Biochemistry and Molecular Biology (SEBBM), celebrado en Madrid del 16 al 19 de julio de 2019., La deficiencia humana del factor de crecimiento similar a la insulina tipo 1 (IGF-1) causa una enfermedad rara (ORPHA 73272) que cursa con retraso en el crecimiento, microcefalia y sordera neurosensorial. El modelo murino deficiente en Igf1 reproduce el mismo síndrome y presenta una incorrecta diferenciación neuronal del ganglio auditivo acompañada de apoptosis temprana de las neuronas auditivas. El estudio del papel protector que ejerce el IGF-1 frente a la pérdida auditiva es complicado por la heterogeneidad celular de la cóclea y la limitación de los modelos experimentales disponibles. Como consecuencia, se ha generado un modelo celular de la enfermedad humana en la línea de neuroblastoma murino Neuro2a mediante edición génica con CRISPR/Cas9. Dicho modelo reproduce la deleción parcial del exón 3 del gen Igf1 murino descrita como causante de pérdida auditiva en el hombre. Para la edición génica se transfectó el complejo crRNA:tracrRNA:Cas9 en forma de ribonucleoproteína y se comprobó su incorporación en las células mediante microscopía detectando el tracrRNA marcado fluorescentemente. La presencia de mutaciones se evaluó mediante Surveyor y se seleccionaron las células mutadas tras clonación por dilución límite. La edición del gen Igf1 se comprobó por PCR en 56 clones y 5 de ellos se secuenciaron mediante el méetodo Sanger, confirmándose la deleción parcial de Igf1 en dos de los clones. Para el resto se emplearía la herramienta Mosaic Finder, desarrollada in-house, que permite analizar la multiplicidad alélica generada tras la edición genética mediante next-generation sequencing (NGS) y posterior análisis bioinformático. Finalmente, se ha iniciado un estudio del estado neuroinflamatorio de los clones secuenciados y de su respuesta a distintos estímulos pro-inflamatorios, que puede contribuir a desvelar algunos mecanismos moleculares asociados a la deficiencia crónica de IGF-1., Agradecimientos: ACCI2016 (ER16P5AC7091); ACCI2017 (ER17P5AC7611) y ACCI2018 (ER19P5AC761).

Published
2019

33. Generación y caracterización de nuevos modelos celulares asociados al deficit neural en IGF-1

Author

Asociación Española Contra el Cáncer, Rodriguez-de la Rosa, Lourdes, García-Mato, Ángela, Vandenbroucke, Roosmarijn, Morin, Matias, Moreno-Pelayo, Miguel Ángel, Montoliu, Lluís, Varela-Nieto, Isabel, Asociación Española Contra el Cáncer, Rodriguez-de la Rosa, Lourdes, García-Mato, Ángela, Vandenbroucke, Roosmarijn, Morin, Matias, Moreno-Pelayo, Miguel Ángel, Montoliu, Lluís, and Varela-Nieto, Isabel

Abstract

La deficiencia humana del factor de crecimiento similar a la insulina tipo 1 (IGF-1) causa una enfermedad rara (ORPHA 73272) que cursa con retraso en el crecimiento, microcefalia y sordera neurosensorial. El modelo murino deficiente en Igf1 reproduce el mismo síndrome y presenta una incorrecta diferenciación neuronal del ganglio auditivo acompañada de apoptosis temprana de las neuronas auditivas. El estudio del papel protector que ejerce el IGF-1 frente a la pérdida auditiva es complicado por la heterogeneidad celular de la cóclea y la limitación de los modelos experimentales disponibles. Como consecuencia, se ha generado un modelo celular de la enfermedad humana en la línea de neuroblastoma murino Neuro2a mediante edición génica con CRISPR/Cas9. Dicho modelo reproduce la deleción parcial del exón 3 del gen Igf1 murino descrita como causante de pérdida auditiva en el hombre. Para la edición génica se transfectó el complejo crRNA:tracrRNA:Cas9 en forma de ribonucleoproteína y se comprobó su incorporación en las células mediante microscopía detectando el tracrRNA marcado fluorescentemente. La presencia de mutaciones se evaluó mediante Surveyor y se seleccionaron las células mutadas tras clonación por dilución límite. La edición del gen Igf1 se comprobó por PCR en 56 clones y 5 de ellos se secuenciaron mediante el méetodo Sanger, confirmándose la deleción parcial de Igf1 en dos de los clones. Para el resto se emplearía la herramienta Mosaic Finder, desarrollada in-house, que permite analizar la multiplicidad alélica generada tras la edición genética mediante next-generation sequencing (NGS) y posterior análisis bioinformático. Finalmente, se ha iniciado un estudio del estado neuroinflamatorio de los clones secuenciados y de su respuesta a distintos estímulos pro-inflamatorios, que puede contribuir a desvelar algunos mecanismos moleculares asociados a la deficiencia crónica de IGF-1.

Published
2019

35. Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel

Author

Shen, Jun, primary, Oza, Andrea M., additional, del Castillo, Ignacio, additional, Duzkale, Hatice, additional, Matsunaga, Tatsuo, additional, Pandya, Arti, additional, Kang, Hyunseok P., additional, Mar-Heyming, Rebecca, additional, Guha, Saurav, additional, Moyer, Krista, additional, Lo, Christine, additional, Kenna, Margaret, additional, Alexander, John J., additional, Zhang, Yan, additional, Hirsch, Yoel, additional, Luo, Minjie, additional, Cao, Ye, additional, Wai Choy, Kwong, additional, Cheng, Yen-Fu, additional, Avraham, Karen B., additional, Hu, Xinhua, additional, Garrido, Gema, additional, Moreno-Pelayo, Miguel A., additional, Greinwald, John, additional, Zhang, Kejian, additional, Zeng, Yukun, additional, Brownstein, Zippora, additional, Basel-Salmon, Lina, additional, Davidov, Bella, additional, Frydman, Moshe, additional, Weiden, Tzvi, additional, Nagan, Narasimhan, additional, Willis, Alecia, additional, Hemphill, Sarah E., additional, Grant, Andrew R., additional, Siegert, Rebecca K., additional, DiStefano, Marina T., additional, Amr, Sami S., additional, Rehm, Heidi L., additional, Abou Tayoun, Ahmad N., additional, Azaiez, Hela, additional, Booth, Kevin T., additional, Smith, Richard J., additional, Giersch, Anne B., additional, Morton, Cynthia C., additional, Liu, Xue Z., additional, Tekin, Mustafa, additional, Lu, Yu, additional, Yuan, Huijun, additional, Mutai, Hideki, additional, and Schimmenti, Lisa, additional

Published
2019
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36. Correction: ClinGen expert clinical validity curation of 164 hearing loss gene–disease pairs

Author

DiStefano, Marina T., primary, Hemphill, Sarah E., additional, Oza, Andrea M., additional, Siegert, Rebecca K., additional, Grant, Andrew R., additional, Hughes, Madeline Y., additional, Cushman, Brandon J., additional, Azaiez, Hela, additional, Booth, Kevin T., additional, Chapin, Alex, additional, Duzkale, Hatice, additional, Matsunaga, Tatsuo, additional, Shen, Jun, additional, Zhang, Wenying, additional, Kenna, Margaret, additional, Schimmenti, Lisa A., additional, Tekin, Mustafa, additional, Rehm, Heidi L., additional, Tayoun, Ahmad N. Abou, additional, Amr, Sami S., additional, Abdelhak, Sonia, additional, Alexander, John, additional, Avraham, Karen, additional, Bhatia, Neha, additional, Bai, Donglin, additional, Boczek, Nicole, additional, Brownstein, Zippora, additional, Burt, Rachel, additional, Bylstra, Yasmin, additional, del Castillo, Ignacio, additional, Choi, Byung Yoon, additional, Downie, Lilian, additional, Friedman, Thomas, additional, Giersch, Anne, additional, Goh, Jasmine, additional, Greinwald, John, additional, Griffith, Andrew J., additional, Hernandez, Amy, additional, Holt, Jeffrey, additional, Hosoya, Makoto, additional, Ying, Lim Jiin, additional, Jain, Kanika, additional, Kim, Un-Kyung, additional, Kremer, Hannie, additional, Krantz, Ian, additional, Leal, Suzanne, additional, Lewis, Morag, additional, Liu, Xue Zhong, additional, Low, Wendy, additional, Lu, Yu, additional, Luo, Minjie, additional, Masmoudi, Saber, additional, Ming, Tan Yuen, additional, Moreno-Pelayo, Miguel Angel, additional, Morín, Matías, additional, Morton, Cynthia, additional, Murray, Jaclyn, additional, Mutai, Hideki, additional, Nara, Kiyomitsu, additional, Pandya, Arti, additional, Pei-Rong, Sylvia Kam, additional, Smith, Richard J.H., additional, Jamuar, Saumya Shekhar, additional, Suer, Funda Elif, additional, Usami, Shin-Ichi, additional, Van Camp, Guy, additional, Yamazawa, Kazuki, additional, Yuan, Hui-Jun, additional, Black-Zeigelbein, Elizabeth, additional, and Zhang, Keijan, additional

Published
2019
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37. ClinGen expert clinical validity curation of 164 hearing loss gene–disease pairs

Author

DiStefano, Marina T., primary, Hemphill, Sarah E., additional, Oza, Andrea M., additional, Siegert, Rebecca K., additional, Grant, Andrew R., additional, Hughes, Madeline Y., additional, Cushman, Brandon J., additional, Azaiez, Hela, additional, Booth, Kevin T., additional, Chapin, Alex, additional, Duzkale, Hatice, additional, Matsunaga, Tatsuo, additional, Shen, Jun, additional, Zhang, Wenying, additional, Kenna, Margaret, additional, Schimmenti, Lisa A., additional, Tekin, Mustafa, additional, Rehm, Heidi L., additional, Tayoun, Ahmad N. Abou, additional, Amr, Sami S., additional, Abdelhak, Sonia, additional, Alexander, John, additional, Avraham, Karen, additional, Bhatia, Neha, additional, Bai, Donglin, additional, Boczek, Nicole, additional, Brownstein, Zippora, additional, Burt, Rachel, additional, Bylstra, Yasmin, additional, del Castillo, Ignacio, additional, Choi, Byung Yoon, additional, Downie, Lilian, additional, Friedman, Thomas, additional, Giersch, Anne, additional, Goh, Jasmine, additional, Greinwald, John, additional, Griffith, Andrew J., additional, Hernandez, Amy, additional, Holt, Jeffrey, additional, Hosoya, Makoto, additional, Ying, Lim Jiin, additional, Jain, Kanika, additional, Kim, Un-Kyung, additional, Kremer, Hannie, additional, Krantz, Ian, additional, Leal, Suzanne, additional, Lewis, Morag, additional, Liu, Xue Zhong, additional, Low, Wendy, additional, Lu, Yu, additional, Luo, Minjie, additional, Masmoudi, Saber, additional, Ming, Tan Yuen, additional, Moreno-Pelayo, Miguel Angel, additional, Morín, Matías, additional, Morton, Cynthia, additional, Murray, Jaclyn, additional, Mutai, Hideki, additional, Nara, Kiyomitsu, additional, Pandya, Arti, additional, Pei-Rong, Sylvia Kam, additional, Smith, Richard J.H., additional, Jamuar, Saumya Shekhar, additional, Suer, Funda Elif, additional, Usami, Shin-Ichi, additional, Van Camp, Guy, additional, Yamazawa, Kazuki, additional, Yuan, Hui-Jun, additional, Black-Zeigelbein, Elizabeth, additional, and Zhang, Keijan, additional

Published
2019
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39. Differential contribution of HLA-DR, DQ, and TAP2 alleles to systemic lupus erythematosus susceptibility in Spanish patients: role of TAP2*01 alleles in Ro autoantibody production

Author

Martin-Villa, Jose M., Martinez-Laso, Jorge, Moreno-Pelayo, Miguel A., Castro-Panete, Maria J., Martinez-Quiles, Narcisa, Alvarez, Miguel, De Juan, Maria D., Gomez-Reino, Juan J., and Arnaiz-Villena, Antonio

Subjects
Systemic lupus erythematosus -- Genetic aspects, Spaniards -- Health aspects, HLA class II antigens -- Health aspects, Health
Abstract

Particular genes may be associated with increased risk and severity of systemic lupus erythematosus (SLE) in Spanish people. SLE is an autoimmune disease. Researchers in Spain compared genetic profiles of 85 people with SLE and 186 healthy volunteers. Particular human leukocyte antigen (HLA) genes were more common in SLE patients, and associated with kidney damage from the disease. The genes which related to SLE in Spanish patients were different than those associated with the disease in other ethnic groups.

Published
1998

40. Efficient CRISPR/Cas9-Mediated Gene Editing of Pklr in Human Hematopoietic Progenitors and Stem Cells for the Gene Therapy of Pyruvate Kinase Deficiency

Author

Quintana Bustamante, Oscar, primary, Fañanas-Baquero, Sara, additional, Dever, Daniel P., additional, Omaira, Alberquilla, additional, Camarena, Joab, additional, Sanchez-Dominguez, Rebeca, additional, Morin, Matias, additional, Fernandez, Val, additional, Moreno-Pelayo, Miguel Angel, additional, Bueren, Juan A., additional, Porteus, Matthew, additional, and Segovia, Jose C, additional

Published
2018
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41. Parental Mosaicism in PAX6 Causes Intra-Familial Variability: Implications for Genetic Counseling of Congenital Aniridia and Microphthalmia

Author

Tarilonte, María, primary, Morín, Matías, additional, Ramos, Patricia, additional, Galdós, Marta, additional, Blanco-Kelly, Fiona, additional, Villaverde, Cristina, additional, Rey-Zamora, Dolores, additional, Rebolleda, Gema, additional, Muñoz-Negrete, Francisco J., additional, Tahsin-Swafiri, Saoud, additional, Gener, Blanca, additional, Moreno-Pelayo, Miguel-Angel, additional, Ayuso, Carmen, additional, Villamar, Manuela, additional, and Corton, Marta, additional

Published
2018
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42. Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymmetric and Unilateral Hearing Loss and Waardenburg Syndrome Type 2

Author

Zazo Seco, Celia, Serrão de Castro, Luciana, van Nierop, Josephine W, Morín, Matías, Jhangiani, Shalini, Verver, Eva J J, Schraders, Margit, Maiwald, Nadine, Wesdorp, Mieke, Venselaar, Hanka, Spruijt, Liesbeth, Oostrik, Jaap, Schoots, Jeroen, van Reeuwijk, Jeroen, Lelieveld, Stefan H, Huygen, Patrick L M, Insenser, María, Admiraal, Ronald J C, Pennings, Ronald J E, Hoefsloot, Lies H, Arias-Vásquez, Alejandro, de Ligt, Joep, Yntema, Helger G, Jansen, Joop H, Muzny, Donna M, Huls, Gerwin, van Rossum, Michelle M, Lupski, James R, Moreno-Pelayo, Miguel Angel, Kunst, Henricus P M, and Kremer, Hannie

Subjects
Male, Stem Cell Factor, Reverse Transcriptase Polymerase Chain Reaction, Genetic Linkage, Fluorescent Antibody Technique, Hearing Loss, Unilateral, Prognosis, Real-Time Polymerase Chain Reaction, Pedigree, Mice, Phenotype, Mutation, NIH 3T3 Cells, Animals, Humans, Female, Waardenburg Syndrome, RNA, Messenger, Alleles
Abstract

Linkage analysis combined with whole-exome sequencing in a large family with congenital and stable non-syndromic unilateral and asymmetric hearing loss (NS-UHL/AHL) revealed a heterozygous truncating mutation, c.286_303delinsT (p.Ser96Ter), in KITLG. This mutation co-segregated with NS-UHL/AHL as a dominant trait with reduced penetrance. By screening a panel of probands with NS-UHL/AHL, we found an additional mutation, c.200_202del (p.His67_Cys68delinsArg). In vitro studies revealed that the p.His67_Cys68delinsArg transmembrane isoform of KITLG is not detectable at the cell membrane, supporting pathogenicity. KITLG encodes a ligand for the KIT receptor. Also, KITLG-KIT signaling and MITF are suggested to mutually interact in melanocyte development. Because mutations in MITF are causative of Waardenburg syndrome type 2 (WS2), we screened KITLG in suspected WS2-affected probands. A heterozygous missense mutation, c.310C>G (p.Leu104Val), that segregated with WS2 was identified in a small family. In vitro studies revealed that the p.Leu104Val transmembrane isoform of KITLG is located at the cell membrane, as is wild-type KITLG. However, in culture media of transfected cells, the p.Leu104Val soluble isoform of KITLG was reduced, and no soluble p.His67_Cys68delinsArg and p.Ser96Ter KITLG could be detected. These data suggest that mutations in KITLG associated with NS-UHL/AHL have a loss-of-function effect. We speculate that the mechanism of the mutation underlying WS2 and leading to membrane incorporation and reduced secretion of KITLG occurs via a dominant-negative or gain-of-function effect. Our study unveils different phenotypes associated with KITLG, previously associated with pigmentation abnormalities, and will thereby improve the genetic counseling given to individuals with KITLG variants.

Published
2015

43. Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymmetric and Unilateral Hearing Loss and Waardenburg Syndrome Type 2

Author

Zazo Seco, Celia, primary, Serrão de Castro, Luciana, additional, van Nierop, Josephine W., additional, Morín, Matías, additional, Jhangiani, Shalini, additional, Verver, Eva J.J., additional, Schraders, Margit, additional, Maiwald, Nadine, additional, Wesdorp, Mieke, additional, Venselaar, Hanka, additional, Spruijt, Liesbeth, additional, Oostrik, Jaap, additional, Schoots, Jeroen, additional, van Reeuwijk, Jeroen, additional, Lelieveld, Stefan H., additional, Huygen, Patrick L.M., additional, Insenser, María, additional, Admiraal, Ronald J.C., additional, Pennings, Ronald J.E., additional, Hoefsloot, Lies H., additional, Arias-Vásquez, Alejandro, additional, de Ligt, Joep, additional, Yntema, Helger G., additional, Jansen, Joop H., additional, Muzny, Donna M., additional, Huls, Gerwin, additional, van Rossum, Michelle M., additional, Lupski, James R., additional, Moreno-Pelayo, Miguel Angel, additional, Kunst, Henricus P.M., additional, and Kremer, Hannie, additional

Published
2015
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44. Mutations in PRPS1 causing syndromic or nonsyndromic hearing impairment: intrafamilial phenotypic variation complicates genetic counseling

Author

Gandía, Marta, primary, Fernández-Toral, Joaquín, additional, Solanellas, Juan, additional, Domínguez-Ruiz, María, additional, Gómez-Rosas, Elena, additional, del Castillo, Francisco J., additional, Villamar, Manuela, additional, Moreno-Pelayo, Miguel A., additional, and del Castillo, Ignacio, additional

Published
2015
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46. A novel KCNQ4 pore-region mutation (p.G296S) causes deafness by impairing cell-surface channel expression

Author

Mencía, Á., González-Nieto, Daniel, Modamio-Høybjør, S., Etxeberría, Ainhoa, Aránguez, Gracia, Salvador Cabos, Nieves, Castillo, I., Villarroel, Álvaro, Moreno, F., Barrio, Luis, Moreno-Pelayo, Miguel Ángel, Mencía, Á., González-Nieto, Daniel, Modamio-Høybjør, S., Etxeberría, Ainhoa, Aránguez, Gracia, Salvador Cabos, Nieves, Castillo, I., Villarroel, Álvaro, Moreno, F., Barrio, Luis, and Moreno-Pelayo, Miguel Ángel

Abstract

Mutations in the potassium channel gene KCNQ4 underlie DFNA2, a subtype of autosomal dominant progressive, high-frequency hearing loss. Based on a phenotype-guided mutational screening we have identified a novel mutation c.886G>A, leading to the p.G296S substitution in the pore region of KCNQ4 channel. The possible impact of this mutation on total KCNQ4 protein expression, relative surface expression and channel function was investigated. When the G296S mutant was expressed in Xenopus oocytes, electrophysiological recordings did not show voltage-activated K+ currents. The p.G296S mutation impaired KCNQ4 channel activity in two manners. It greatly reduced surface expression and, secondarily, abolished channel function. The deficient expression at the cell surface membrane was further confirmed in non-permeabilized NIH-3T3 cells transfected with the mutant KCNQ4 tagged with the hemagglutinin epitope in the extracellular S1-S2 linker. Co-expression of mutant and wild type KCNQ4 in oocytes was performed to mimic the heterozygous condition of the p.G296S mutation in the patients. The results showed that the G296S mutant exerts a strong dominant-negative effect on potassium currents by reducing the wild type KCNQ4 channel expression at the cell surface. This is the first study to identify a trafficking-dependent dominant mechanism for the loss of KCNQ4 channel function in DFNA2. © Springer-Verlag 2007.

Published
2008

48. A novel KCNQ4 pore-region mutation (p.G296S) causes deafness by impairing cell-surface channel expression

Author

Mencía, Ángeles, primary, González-Nieto, Daniel, additional, Modamio-Høybjør, Silvia, additional, Etxeberría, Ainhoa, additional, Aránguez, Gracia, additional, Salvador, Nieves, additional, del Castillo, Ignacio, additional, Villarroel, Álvaro, additional, Moreno, Felipe, additional, Barrio, Luis, additional, and Moreno-Pelayo, Miguel Ángel, additional

Published
2007
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49. Three New Mutations and Mild, Asymmetrical Phenotype in the Highly Distinctive LAMM Syndrome: A Report of Eight Further Cases.

Author

Al Yassin, Amina, D'Arco, Felice, Morín, Matías, Pagarkar, Waheeda, Harrop-Griffiths, Katherine, Shaida, Azhar, Fernández, Elena, Cullup, Tom, De-Souza, Bianca, Moreno-Pelayo, Miguel Angel, and Bitner-Glindzicz, Maria

Subjects
RECESSIVE genes, SYNDROMES, PHENOTYPES, INNER ear, NEMALINE myopathy, DEAFNESS, CONSANGUINITY
Abstract

Labyrinthine aplasia, microtia, and microdontia (LAMM) is an autosomal recessive condition causing profound congenital deafness, complete absence of inner ear structures (usually Michel's aplasia), microtia (usually type 1) and microdontia. To date, several families have been described with this condition and a number of mutations has been reported. We report on eight further cases of LAMM syndrome including three novel mutations, c. 173T>C p.L58P; c. 284G>A p.(Arg95Gln) and c.325_327delinsA p.(Glu109Thrfs*18). Congenital deafness was the primary presenting feature in all affected individuals and consanguinity in all but two families. We compare the features in our patients to those previously reported in LAMM, and describe a milder, asymmetrical phenotype associated with FGF3 mutations. [ABSTRACT FROM AUTHOR]

Published
2019
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50. A multicenter study on the prevalence and spectrum of mutations in the otoferlin gene (OTOF) in subjects with nonsyndromic hearing impairment and auditory neuropathy

Author

Pontificia Universidad Javeriana. Facultad de Medicina. Instituto de Genética Humana, Rodríguez-Ballesteros, Montserrat, Reynoso, Raúl, Olarte Giraldo, Margarita María, Villamar López, Manuela, Morera Pérez, Constantino, Santarelli, Rosamaria, Arslan, Edoardo, Medá, Carme, Curet, Carlos Augusto, Völter, Christiane, Sainz-Quevedo, Manuel, Castorina, Pierangela, Ambrosetti, Umberto, Berrettini, Stefano, Frei, Klemens, Tedín García, Socorro, Smith, Janine Margo, Tapia Toca, María Cruz, Cavallé Garrido, Laura, Gelvez Moyano, Nancy Yaneth, Primignani, Paola, Gómez-Rosas, Elena, Martín, Mirta, Moreno Pelayo, Miguel Ángel, Tamayo Fernández, Martha Lucia, Moreno Barral, José, Moreno Herrero, Felipe, Castillo Fernández del Pino, Ignacio del, Pontificia Universidad Javeriana. Facultad de Medicina. Instituto de Genética Humana, Rodríguez-Ballesteros, Montserrat, Reynoso, Raúl, Olarte Giraldo, Margarita María, Villamar López, Manuela, Morera Pérez, Constantino, Santarelli, Rosamaria, Arslan, Edoardo, Medá, Carme, Curet, Carlos Augusto, Völter, Christiane, Sainz-Quevedo, Manuel, Castorina, Pierangela, Ambrosetti, Umberto, Berrettini, Stefano, Frei, Klemens, Tedín García, Socorro, Smith, Janine Margo, Tapia Toca, María Cruz, Cavallé Garrido, Laura, Gelvez Moyano, Nancy Yaneth, Primignani, Paola, Gómez-Rosas, Elena, Martín, Mirta, Moreno Pelayo, Miguel Ángel, Tamayo Fernández, Martha Lucia, Moreno Barral, José, Moreno Herrero, Felipe, and Castillo Fernández del Pino, Ignacio del

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