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3. Thalamic Foxp2 regulates output connectivity and sensory-motor impairments in a model of Huntington’s Disease

Author

Rodríguez-Urgellés, Ened, Casas-Torremocha, Diana, Sancho-Balsells, Anna, Ballasch, Iván, García-García, Esther, Miquel-Rio, Lluis, Manasanch, Arnau, del Castillo, Ignacio, Chen, Wanqi, Pupak, Anika, Brito, Veronica, Tornero, Daniel, Rodríguez, Manuel J., Bortolozzi, Analia, Sanchez-Vives, Maria V., Giralt, Albert, and Alberch, Jordi

Published
2023
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6. A murine model for the del(GJB6-D13S1830) deletion recapitulating the phenotype of human DFNB1 hearing impairment: generation and functional and histopathological study

Author

Domínguez Ruiz, María, Murillo Cuesta, Silvia, Contreras Rodríguez, Julio, Cantero, Marta, Garrido, Gema, Martín Bernardo, Belén, Gómez Rosas, Elena, Fernández, Almudena, Del Castillo, Francisco J., Montoliu, Lluís, Varela Nieto, Isabel, Del Castillo, Ignacio, Domínguez Ruiz, María, Murillo Cuesta, Silvia, Contreras Rodríguez, Julio, Cantero, Marta, Garrido, Gema, Martín Bernardo, Belén, Gómez Rosas, Elena, Fernández, Almudena, Del Castillo, Francisco J., Montoliu, Lluís, Varela Nieto, Isabel, and Del Castillo, Ignacio

Abstract

Inherited hearing impairment is a remarkably heterogeneous monogenic condition, involving hundreds of genes, most of them with very small (< 1%) epidemiological contributions. The exception is GJB2, the gene encoding connexin‑26 and underlying DFNB1, which is the most frequent type of autosomal recessive non‑syndromic hearing impairment (ARNSHI) in most populations (up to 40% of ARNSHI cases). DFNB1 is caused by different types of pathogenic variants in GJB2, but also by large deletions that keep the gene intact but remove an upstream regulatory element that is essential for its expression. Such large deletions, found in most populations, behave as complete loss‑of‑function variants, usually associated with a profound hearing impairment. By using CRISPR‑Cas9 genetic edition, we have generated a murine model (Dfnb1em274) that reproduces the most frequent of those deletions, del(GJB6‑D13S1830). Dfnb1 em274 homozygous mice are viable, bypassing the embryonic lethality of the Gjb2 knockout, and present a phenotype of profound hearing loss (> 90 dB SPL) that correlates with specific structural abnormalities in the cochlea. We show that Gjb2 expression is nearly abolished and its protein product, Cx26, is nearly absent all throughout the cochlea, unlike previous conditional knockouts in which Gjb2 ablation was not obtained in all cell types. The Dfnb1 em274 model recapitulates the clinical presentation of patients harbouring the del(GJB6‑D13S1830) variant and thus it is a valuable tool to study the pathological mechanisms of DFNB1 and to assay therapies for this most frequent type of human ARNSHI., Depto. de Anatomía y Embriología, Fac. de Veterinaria, TRUE, pub

Published
2024

7. Audibility, speech perception and processing of temporal cues in ribbon synaptic disorders due to OTOF mutations

Author

Santarelli, Rosamaria, del Castillo, Ignacio, Cama, Elona, Scimemi, Pietro, and Starr, Arnold

Subjects
Neurosciences, Pediatric, Assistive Technology, Bioengineering, Aetiology, 2.1 Biological and endogenous factors, Ear, Acoustic Stimulation, Animals, Audiometry, Evoked Response, Auditory Pathways, Auditory Threshold, Cochlea, Cochlear Implantation, Cochlear Microphonic Potentials, Cochlear Nerve, Cues, Genetic Predisposition to Disease, Glutamic Acid, Hearing, Hearing Loss, Humans, Loudness Perception, Membrane Proteins, Mutation, Persons With Hearing Impairments, Phenotype, Reaction Time, Speech Intelligibility, Speech Perception, Synaptic Transmission, Time Factors, Auditory neuropathy, Electrocochleography, Cochlear implant, Hearing aids, Ribbon synaptic disorders, Clinical Sciences, Medical Physiology, Otorhinolaryngology
Abstract

Mutations in the OTOF gene encoding otoferlin result in a disrupted function of the ribbon synapses with impairment of the multivesicular glutamate release. Most affected subjects present with congenital hearing loss and abnormal auditory brainstem potentials associated with preserved cochlear hair cell activities (otoacoustic emissions, cochlear microphonics [CMs]). Transtympanic electrocochleography (ECochG) has recently been proposed for defining the details of potentials arising in both the cochlea and auditory nerve in this disorder, and with a view to shedding light on the pathophysiological mechanisms underlying auditory dysfunction. We review the audiological and electrophysiological findings in children with congenital profound deafness carrying two mutant alleles of the OTOF gene. We show that cochlear microphonic (CM) amplitude and summating potential (SP) amplitude and latency are normal, consistently with a preserved outer and inner hair cell function. In the majority of OTOF children, the SP component is followed by a markedly prolonged low-amplitude negative potential replacing the compound action potential (CAP) recorded in normally-hearing children. This potential is identified at intensities as low as 90 dB below the behavioral threshold. In some ears, a synchronized CAP is superimposed on the prolonged responses at high intensity. Stimulation at high rates reduces the amplitude and duration of the prolonged potentials, consistently with their neural generation. In some children, however, the ECochG response only consists of the SP, with no prolonged potential. Cochlear implants restore hearing sensitivity, speech perception and neural CAP by electrically stimulating the auditory nerve fibers. These findings indicate that an impaired multivesicular glutamate release in OTOF-related disorders leads to abnormal auditory nerve fiber activation and a consequent impairment of spike generation. The magnitude of these effects seems to vary, ranging from no auditory nerve fiber activation to an abnormal generation of EPSPs that occasionally trigger a synchronized electrical activity, resulting in high-threshold CAPs.

Published
2015

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

Author

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

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

Author

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

Published
2019
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10. 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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11. MPZL2, Encoding the Epithelial Junctional Protein Myelin Protein Zero-like 2, Is Essential for Hearing in Man and Mouse

Author

van Dooren, M.F., de Gier, H.H.W., Hoefsloot, E.H., van der Schroeff, M.P., Kant, S.G., Rotteveel, L.J.C., Frints, S.G.M., Hof, J.R., Stokroos, R.J., Vanhoutte, E.K., Admiraal, R.J.C., Feenstra, I., Kremer, H., Kunst, H.P.M., Pennings, R.J.E., Yntema, H.G., van Essen, A.J., Free, R.H., Klein-Wassink, J.S., Wesdorp, Mieke, Murillo-Cuesta, Silvia, Peters, Theo, Celaya, Adelaida M., Oonk, Anne, Schraders, Margit, Oostrik, Jaap, Gomez-Rosas, Elena, Beynon, Andy J., Hartel, Bas P., Okkersen, Kees, Koenen, Hans J.P.M., Weeda, Jack, Lelieveld, Stefan, Voermans, Nicol C., Joosten, Irma, Hoyng, Carel B., Lichtner, Peter, Kunst, Henricus P.M., Feenstra, Ilse, de Bruijn, Suzanne E., Admiraal, Ronald J.C., Yntema, Helger G., van Wijk, Erwin, del Castillo, Ignacio, Serra, Pau, Varela-Nieto, Isabel, Pennings, Ronald J.E., and Kremer, Hannie

Published
2018
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12. Auditory neuropathies and electrocochleography

Author

Santarelli, Rosamaria, del Castillo, Ignacio, and Starr, Arnold

Subjects
Neurosciences, Neurodegenerative, Peripheral Neuropathy, 2.1 Biological and endogenous factors, Aetiology, Ear, Neurological, cochlear potentials, ribbon synapses, inner hair cells, auditory nerve fibers
Abstract

Auditory neuropathy (AN) is a hearing disorder characterized by disruption of temporal coding of acoustic signals in auditory nerve fibres resulting in impairment of auditory perceptions relying on temporal cues (1,2). Mechanisms suggested include both pre-synaptic and post-synaptic disorders affecting inner hair cell (IHC) depolarization, neurotransmitter release from ribbon synapses, spike initiation in auditory nerve terminals, loss of nerve fibres and impaired conduction, all occurring in the presence of normal physiological measures of outer hair cell (OHC) activities (otoacoustic emissions (OAEs) and cochlear microphonic (CM)). Disordered synchrony of auditory nerve discharge has been suggested as the basis of both the profound alterations of auditory brainstem responses (ABRs) and impairment of speech perception (3). We review how electrocochleography (ECochG) can provide detailed information to help define objectively the sites of auditory neural dysfunction as affecting IHC receptor summating potential (SP) and compound action potential (CAP), the latter reflecting disorders of ribbon synapsis and auditory nerve fibres. © 2013 Informa Healthcare.

Published
2013

13. Presynaptic and postsynaptic mechanisms underlying auditory neuropathy in patients with mutations in the OTOF or OPA1 gene

Author

Santarelli, Rosamaria, Starr, Arnold, del Castillo, Ignacio, Huang, Taosheng, Scimemi, Pietro, Cama, Elona, Rossi, Roberta, and Arslan, Edoardo

Subjects
Neurosciences, Clinical Research, Bioengineering, Peripheral Neuropathy, Assistive Technology, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Ear
Abstract

Objective: Our objective was to compare acoustically-and electrically-evoked potentials of the auditory nerve in patients with postsynaptic or presynaptic auditory neuropathy with underlying mutations in the OPA1 or OTOF gene. Study design: Transtympanic electrocochleography (ECochG) was recorded from two adult patients carrying the R445H OPA1 mutation, and from five children with mutations in the OTOF gene. Cochlear potentials to clicks or tone-bursts were compared to recordings obtained from 16 normally hearing subjects. Electrically-evoked neural responses recorded through the cochlear implant were also obtained. Results: The cochlear microphonic (CM) was recorded from all subjects, with normal amplitudes. After cancelling the CM, cochlear potentials were of negative polarity with reduced amplitude and prolonged duration compared to controls in both groups of patients. Prolonged negative responses were recorded as low as 50-90dB below behavioural threshold in subjects with OTOF mutations whereas in the OPA1 disorder the prolonged potentials were correlated with hearing threshold. A compound action potential (CAP) was superimposed on the prolonged activity at high stimulation intensity in two children with mutations in the OTOF gene while CAPs were absent in the OPA1 disorder. Electrically-evoked compound action potentials (e-CAPs) were only recorded from subjects with OTOF mutations following cochlear implantation. Conclusions: The findings are consistent with abnormal function of distal portions of auditory nerve fibres in patients carrying the OPA1 mutation whereas the low-threshold prolonged potentials recorded from children with mutations in the OTOF gene are consistent with abnormal neurotransmitter release resulting in reduced dendritic activation and impairment of spike initiation. © 2011 Informa Healthcare.

Published
2011

14. Abnormal Cochlear Potentials from Deaf Patients with Mutations in the Otoferlin Gene

Author

Santarelli, Rosamaria, del Castillo, Ignacio, Rodríguez-Ballesteros, Montserrat, Scimemi, Pietro, Cama, Elona, Arslan, Edoardo, and Starr, Arnold

Subjects
Neurosciences, Clinical Research, Assistive Technology, Bioengineering, Peripheral Neuropathy, Aetiology, 2.1 Biological and endogenous factors, Ear, Neurological, Acoustic Stimulation, Audiometry, Pure-Tone, Auditory Threshold, Cochlear Microphonic Potentials, Cochlear Nerve, Deafness, Evoked Potentials, Auditory, Brain Stem, Female, Hair Cells, Auditory, Inner, Humans, Infant, Male, Mechanotransduction, Cellular, Membrane Proteins, Mutation, non-syndromic hearing impairment, auditory neuropathy, otoferlin, compound action potential, cochlear microphonic, summating potential, Clinical Sciences, Otorhinolaryngology
Abstract

Otoferlin is involved in neurotransmitter release at the synapse between inner hair cells (IHCs) and auditory nerve fibres, and mutations in the OTOF gene result in severe to profound hearing loss. Abnormal sound-evoked cochlear potentials were recorded with transtympanic electrocochleography from four children with otoferlin (OTOF) mutations to evaluate physiological effects in humans of abnormal neurotransmitter release from IHCs. The subjects were profoundly deaf with absent auditory brainstem responses and preserved otoacoustic emissions consistent with auditory neuropathy. Two children were compound heterozygotes for mutations c.2732_2735dupAGCT and p.Ala964Glu; one subject was homozygous for mutation p.Phe1795Cys, and one was compound heterozygote for two novel mutations c.1609delG in exon 16 and c.1966delC in exon 18. Cochlear potentials evoked by clicks from 60 to 120 dB peak equivalent sound pressure level were compared to recordings obtained from 16 normally hearing children. Cochlear microphonic (CM) was recorded with normal amplitudes from all but one ear. After cancelling CM, cochlear potentials were of negative polarity with reduced amplitude and prolonged duration compared to controls. These cochlear potentials were recorded as low as 50-90 dB below behavioural thresholds in contrast to the close correlation in controls between cochlear potentials and behavioural threshold. Summating potential was identified in five out of eight ears with normal latency whilst auditory nerve compound action potentials were either absent or of low amplitude. Stimulation at high rates reduced amplitude and duration of the prolonged potentials, consistent with neural generation. This study suggests that mechano-electrical transduction and cochlear amplification are normal in patients with OTOF mutations. The low-amplitude prolonged negative potentials are consistent with decreased neurotransmitter release resulting in abnormal dendritic activation and impairment of auditory nerve firing.

Published
2009

17. 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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20. Thalamic Foxp2 regulates output connectivity and sensory-motor impairments in a model of Huntington's Disease

Author

Conferencia de Rectores de las Universidades Españolas, Consejo Superior de Investigaciones Científicas (España), European Commission, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Generalitat de Catalunya, Giralt, Albert [0000-0001-5334-0963], Rodríguez-Urgellés, Ened, Casas-Torremocha, Diana, Sancho-Balsells, Anna, Ballasch, Iván, García-García, Esther, Miquel-Rio, Lluis, Manasanch, Arnau, Del Castillo, Ignacio, Chen, Wanqi, Pupak, Anika, Brito, Veronica, Tornero, Daniel, Rodríguez, Manuel J., Bortolozzi, Analía, Sanchez-Vives, Maria V., Giralt, Albert, Alberch, Jordi, Conferencia de Rectores de las Universidades Españolas, Consejo Superior de Investigaciones Científicas (España), European Commission, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Generalitat de Catalunya, Giralt, Albert [0000-0001-5334-0963], Rodríguez-Urgellés, Ened, Casas-Torremocha, Diana, Sancho-Balsells, Anna, Ballasch, Iván, García-García, Esther, Miquel-Rio, Lluis, Manasanch, Arnau, Del Castillo, Ignacio, Chen, Wanqi, Pupak, Anika, Brito, Veronica, Tornero, Daniel, Rodríguez, Manuel J., Bortolozzi, Analía, Sanchez-Vives, Maria V., Giralt, Albert, and Alberch, Jordi

Abstract

Huntington's Disease (HD) is a disorder that affects body movements. Altered glutamatergic innervation of the striatum is a major hallmark of the disease. Approximately 30% of those glutamatergic inputs come from thalamic nuclei. Foxp2 is a transcription factor involved in cell differentiation and reported low in patients with HD. However, the role of the Foxp2 in the thalamus in HD remains unexplored.

Published
2023

22. 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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23. Tryptophan‐rich basic protein (WRB) mediates insertion of the tail‐anchored protein otoferlin and is required for hair cell exocytosis and hearing

Author

Vogl, Christian, Panou, Iliana, Yamanbaeva, Gulnara, Wichmann, Carolin, Mangosing, Sara J, Vilardi, Fabio, Indzhykulian, Artur A, Pangršič, Tina, Santarelli, Rosamaria, Rodriguez‐Ballesteros, Montserrat, Weber, Thomas, Jung, Sangyong, Cardenas, Elena, Wu, Xudong, Wojcik, Sonja M, Kwan, Kelvin Y, del Castillo, Ignacio, Schwappach, Blanche, Strenzke, Nicola, Corey, David P, Lin, Shuh‐Yow, and Moser, Tobias

Published
2016
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27. 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

28. Adapting ChatBot to virtual avatars with Metahuman ChatBot communication with Unreal Engine and Text-To-Speech conversion with ReadSpeaker API

Author

Jiménez del Castillo, Ignacio, Bueno Vallejo, David, and Lenguajes y Ciencias de la Computación

Subjects
Grado en Ingeniería Informática - Trabajos Fin de Grado, Avatares 3D, Voz - Reconocimiento automático, Proceso óptico de datos, ReadSpeaker, Unreal Engine, Text-To-Speech, Visemas, Visualización tridimensional (Informática), Informática - Trabajos Fin de Grado, ChatBot, Tecnologías - Aspectos sociales
Abstract

En la actualidad se está extendiendo el uso de chatbots y asistentes a través de páginas web, whatsapp, algunos con voz como el Asistente de Google, Cortana o Siri. A todos ellos les falta un toque más humano que daría una interfaz 3D. En este proyecto se ha trabajado para dar una interfaz 3D genérica en formato de Avatar a esos chatbots. Utilizando tecnologías de texto a voz, analizando los movimientos de la boca que estarían asociados a cada sonido (visema) para generar una interacción en tiempo real lo más realista posible. Este Proyecto ha consistido en el desarrollo de un avatar virtual 3D en Unreal Engine 4 utilizando la nueva tecnología MetaHumans. Este avatar puede conectarse con un chatbot y, utilizando la tecnología ReadSpeaker Text to Speech, puede obtener los pares de audio y duración de visema a partir de la respuesta del chatbot. El avatar utiliza estos resultados para generar una animación facial de la respuesta. Este TFG en concreto se encarga del envío del texto al Chatbot así como del procesamiento de la respuesta para obtener el audio y la información de los visemas. Todo esto se hace con el propósito de ofrecer a los usuarios de este tipo de servicios una experiencia más realista, aprovechando las tecnologías más modernas de generación de voz y creación de avatares virtuales. En la memoria también se detallará como utilizar cada tecnología que ha sido empleada para el desarrollo de este proyecto, ya que gran parte de este ha consistido en aprender a utilizar tecnologías que se encuentran todavía en desarrollo.

Published
2022

29. 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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34. 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

35. Mutation in TRMU related to transfer RNA modification modulates the phenotypic expression of the deafness-associated mitochondrial 12S ribosomal RNA mutations

Author

Min-Xin Guan, Qingfeng Yan, Xiaoming Li, Bykhovaskaya, Yelena, Gallo-Teran, Jaime, Hajek, Petr, Umeda, Noriko, Hui Zhao, Garrido, Gema, Mengesha, Emebet, Suzuki, Tsutomu, del Castillo, Ignacio, Peters, Jennifer Lynne, Ronghua Li, Yaping Qian; Xinjian Wang, Ballana, Ester, Watanabe, Kimitsuna, Shohat, Mordechai, Jianxin Lu; Estivill, Xavier, and Fischel-Ghodsian, Nathan

Subjects
Gene mutations -- Research, Ribosomal RNA -- Research, Mitochondrial DNA -- Research, Biological sciences
Abstract

The nuclear-modifier genes are found to modulate the phenotypic manifestation of the A1555G mutation and the nuclear-modifier gene TRMU, which encodes a highly conserved mitochondrial protein related to transfer RNA (tRNA) modification, is identified. The results have shown that the mutated TRMU, which acts as a modifier factor, modulates the phenotypic manifestation of the deafness-associated 12S ribosomal RNA (rRNA) mutations.

Published
2006

38. GJB2 mutations and degree of hearing loss: a multicenter study

Author

Snoeckx, Rikkert L., Huygen, Patrick L.M., Feldmann, Delphine, Marlin, Sandrine, Denoyelle, Francoise, Waligora, Jaroslaw, Mueller-Malesinska, Malgorzata, Pollak, Agneszka, Ploski, Rafal, Murgia, Alessandra, Orzan, Eva, Castorina, Pierangela, Ambrosetti, Umberto, Nowakowska-Szyrwinska, Ewa, Bal, Jerzy, Wiszniewski, Wojciech, Janecke, Andreas R., Nekahm-Heis, Doris, Seeman, Pavel, Bendova, Olga, Kenna, Margaret A., Frangulov, Anna, Rehm, Heidi L., Tekin, Mustafa, Incesulu, Armagan, Dahl, Hans-Henrik M., du Sart, Desiree, Jenkins, Lucy, Lucas, Deirdre, Bitner-Glindzicz, Maria, Avraham, Karen B., Brownstein, Zippora, del Castillo, Ignacio, Moreno, Felipe, Blin, Nikolaus, Pfister, Markus, Sziklai, Istvan, Toth, Timea, Kelley, Philip M., Cohn, Edward S., Van Maldergem, Lionel, Hilbert, Pascale, Roux, Anne-Francoise, Mondain, Michel, Hoefsloot, Lies H., Cremers, Cor W.R.J., Lopponen, Tuija, Lopponen, Heikki, Parving, Agnete, Gronskov, Karen, Schrijver, Iris, Roberson, Joseph, Gualandi, Francesca, Martini, Alessandro, Lina-Granade, Genevieve, Pallares-Ruiz, Nathalie, Correia, Ceu, Fialho, Graca, Cryns, Kim, Hilgert, Nele, Van de Heyning, Paul, Nishimura, Carla J., Smith, Richard J.H., and Van Camp, Guy

Subjects
Hearing disorders -- Case studies, Human genetics -- Research, Biological sciences
Published
2005

40. 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

41. Construction and characterization of mutations at codon 751 of the Escherichia coli gyrB gene that confer resistance to the antimicrobial peptide microcin B17 and alter the activity of DNA gyrase

Author

del Castillo, Francisco J., del Castillo, Ignacio, and Moreno, Felipe

Subjects
Mutagenicity testing -- Testing, DNA topoisomerase II -- Analysis, Amino acids -- Structure-activity relationships, Antibiotics -- Physiological aspects, Biological sciences
Abstract

Site-directed mutagenesis of DNA gyrase, in which tryptophan 751 is replaced by arginine, alters the enzyme's DNA replication activity and confers different levels of resistance to the peptide antibiotic microcin B17.

Published
2001

42. DFNA8/12 caused by TECTA mutations is the most identified subtype of nonsyndromic autosomal dominant hearing loss

Author

Hildebrand, Michael S., Morín, Matías, Meyer, Nicole C., Mayo, Fernando, Modamio-Hoybjor, Silvia, Mencía, Angeles, Olavarrieta, Leticia, Morales-Angulo, Carmelo, Nishimura, Carla J., Workman, Heather, DeLuca, Adam P., del Castillo, Ignacio, Taylor, Kyle R., Tompkins, Bruce, Goodman, Corey W., Schrauwen, Isabelle, Van Wesemael, Maarten, Lachlan, K., Shearer, Eliot A., Braun, Terry A., Huygen, Patrick L.M., Kremer, Hannie, Van Camp, Guy, Moreno, Felipe, Casavant, Thomas L., Smith, Richard J.H., and Moreno-Pelayo, Miguel A.

Published
2011
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46. 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

Rodríguez-Ballesteros, Montserrat, Reynoso, Raúl, Olarte, Margarita, Villamar, Manuela, Morera, Constantino, Santarelli, Rosamaria, Arslan, Edoardo, Medá, Carme, Curet, Carlos, Völter, Christiane, Sainz-Quevedo, Manuel, Castorina, Pierangela, Ambrosetti, Umberto, Berrettini, Stefano, Frei, Klemens, Tedín, Socorro, Smith, Janine, Tapia, Cruz M., Cavallé, Laura, Gelvez, Nancy, Primignani, Paola, Gómez-Rosas, Elena, Martín, Mirta, Moreno-Pelayo, Miguel A., Tamayo, Martalucía, Moreno-Barral, José, Moreno, Felipe, and del Castillo, Ignacio

Published
2008
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