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43 results on '"Verdura, Edgard"'

1. ClinPrior: an algorithm for diagnosis and novel gene discovery by network-based prioritization

Author

Schlüter, Agatha, Vélez-Santamaría, Valentina, Verdura, Edgard, Rodríguez-Palmero, Agustí, Ruiz, Montserrat, Fourcade, Stéphane, Planas-Serra, Laura, Launay, Nathalie, Guilera, Cristina, Martínez, Juan José, Homedes-Pedret, Christian, Albertí-Aguiló, M. Antonia, Zulaika, Miren, Martí, Itxaso, Troncoso, Mónica, Tomás-Vila, Miguel, Bullich, Gemma, García-Pérez, M. Asunción, Sobrido-Gómez, María-Jesús, López-Laso, Eduardo, Fons, Carme, Del Toro, Mireia, Macaya, Alfons, Beltran, Sergi, Gutiérrez-Solana, Luis G., Pérez-Jurado, Luis A., Aguilera-Albesa, Sergio, de Munain, Adolfo López, Casasnovas, Carlos, and Pujol, Aurora

Published
2023
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2. Clinical and Molecular Profiling in GNAO1 Permits Phenotype–Genotype Correlation.

Author

Lasa‐Aranzasti, Amaia, Larasati, Yonika A., da Silva Cardoso, Juliana, Solis, Gonzalo P., Koval, Alexey, Cazurro‐Gutiérrez, Ana, Ortigoza‐Escobar, Juan Dario, Miranda, Maria Concepción, De la Casa‐Fages, Beatriz, Moreno‐Galdó, Antonio, Tizzano, Eduardo F., Gómez‐Andrés, David, Verdura, Edgard, Katanaev, Vladimir L., Pérez‐Dueñas, Belén, Cancho Candela, Ramón, Martinez, Jorge Pantoja, Cáceres‐Marzal, Cristina, Martí Carrera, Itxaso, and Duat‐Rodriguez, Ana

Abstract

Background: Defects in GNAO1, the gene encoding the major neuronal G‐protein Gαo, are related to neurodevelopmental disorders, epilepsy, and movement disorders. Nevertheless, there is a poor understanding of how molecular mechanisms explain the different phenotypes. Objectives: We aimed to analyze the clinical phenotype and the molecular characterization of GNAO1‐related disorders. Methods: Patients were recruited in collaboration with the Spanish GNAO1 Association. For patient phenotyping, direct clinical evaluation, analysis of homemade‐videos, and an online questionnaire completed by families were analyzed. We studied Gαo cellular expression, the interactions of the partner proteins, and binding to guanosine triphosphate (GTP) and G‐protein‐coupled receptors (GPCRs). Results: Eighteen patients with GNAO1 genetic defects had a complex neurodevelopmental disorder, epilepsy, central hypotonia, and movement disorders. Eleven patients showed neurological deterioration, recurrent hyperkinetic crisis with partial recovery, and secondary complications leading to death in three cases. Deep brain stimulation improved hyperkinetic crisis, but had inconsistent benefits in dystonia. The molecular defects caused by pathogenic Gαo were aberrant GTP binding and hydrolysis activities, an inability to interact with cellular binding partners, and reduced coupling to GPCRs. Decreased localization of Gαo in the plasma membrane was correlated with the phenotype of "developmental and epileptic encephalopathy 17." We observed a genotype–phenotype correlation, pathogenic variants in position 203 were related to developmental and epileptic encephalopathy, whereas those in position 209 were related to neurodevelopmental disorder with involuntary movements. Milder phenotypes were associated with other molecular defects such as del.16q12.2q21 and I344del. Conclusion: We highlight the complexity of the motor phenotype, which is characterized by fluctuations throughout the day, and hyperkinetic crisis with a distinct post‐hyperkinetic crisis state. We confirm a molecular‐based genotype–phenotype correlation for specific variants. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Published
2024
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3. DLG4-related synaptopathy: a new rare brain disorder

Author

Rodríguez-Palmero, Agustí, Boerrigter, Melissa Maria, Gómez-Andrés, David, Aldinger, Kimberly A., Marcos-Alcalde, Íñigo, Popp, Bernt, Everman, David B., Lovgren, Alysia Kern, Arpin, Stephanie, Bahrambeigi, Vahid, Beunders, Gea, Bisgaard, Anne-Marie, Bjerregaard, V. A., Bruel, Ange-Line, Challman, Thomas D., Cogné, Benjamin, Coubes, Christine, de Man, Stella A., Denommé-Pichon, Anne-Sophie, Dye, Thomas J., Elmslie, Frances, Feuk, Lars, García-Miñaúr, Sixto, Gertler, Tracy, Giorgio, Elisa, Gruchy, Nicolas, Haack, Tobias B., Haldeman-Englert, Chad R., Haukanes, Bjørn Ivar, Hoyer, Juliane, Hurst, Anna C. E., Isidor, Bertrand, Soller, Maria Johansson, Kushary, Sulagna, Kvarnung, Malin, Landau, Yuval E., Leppig, Kathleen A., Lindstrand, Anna, Kleinendorst, Lotte, MacKenzie, Alex, Mandrile, Giorgia, Mendelsohn, Bryce A., Moghadasi, Setareh, Morton, Jenny E., Moutton, Sebastien, Müller, Amelie J., O’Leary, Melanie, Pacio-Míguez, Marta, Palomares-Bralo, Maria, Parikh, Sumit, Pfundt, Rolph, Pode-Shakked, Ben, Rauch, Anita, Repnikova, Elena, Revah-Politi, Anya, Ross, Meredith J., Ruivenkamp, Claudia A. L., Sarrazin, Elisabeth, Savatt, Juliann M., Schlüter, Agatha, Schönewolf-Greulich, Bitten, Shad, Zohra, Shaw-Smith, Charles, Shieh, Joseph T., Shohat, Motti, Spranger, Stephanie, Thiese, Heidi, Mau-Them, Frederic Tran, van Bon, Bregje, van de Burgt, Ineke, van de Laar, Ingrid M. B. H., van Drie, Esmée, van Haelst, Mieke M., van Ravenswaaij-Arts, Conny M., Verdura, Edgard, Vitobello, Antonio, Waldmüller, Stephan, Whiting, Sharon, Zweier, Christiane, Prada, Carlos E., de Vries, Bert B. A., Dobyns, William B., Reiter, Simone F., Gómez-Puertas, Paulino, Pujol, Aurora, and Tümer, Zeynep

Published
2021
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4. Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder

Author

Kour, Sukhleen, Rajan, Deepa S., Fortuna, Tyler R., Anderson, Eric N., Ward, Caroline, Lee, Youngha, Lee, Sangmoon, Shin, Yong Beom, Chae, Jong-Hee, Choi, Murim, Siquier, Karine, Cantagrel, Vincent, Amiel, Jeanne, Stolerman, Elliot S., Barnett, Sarah S., Cousin, Margot A., Castro, Diana, McDonald, Kimberly, Kirmse, Brian, Nemeth, Andrea H., Rajasundaram, Dhivyaa, Innes, A. Micheil, Lynch, Danielle, Frosk, Patrick, Collins, Abigail, Gibbons, Melissa, Yang, Michele, Desguerre, Isabelle, Boddaert, Nathalie, Gitiaux, Cyril, Rydning, Siri Lynne, Selmer, Kaja K., Urreizti, Roser, Garcia-Oguiza, Alberto, Osorio, Andrés Nascimento, Verdura, Edgard, Pujol, Aurora, McCurry, Hannah R., Landers, John E., Agnihotri, Sameer, Andriescu, E. Corina, Moody, Shade B., Phornphutkul, Chanika, Sacoto, Maria J. Guillen, Begtrup, Amber, Houlden, Henry, Kirschner, Janbernd, Schorling, David, Rudnik-Schöneborn, Sabine, Strom, Tim M., Leiz, Steffen, Juliette, Kali, Richardson, Randal, Yang, Ying, Zhang, Yuehua, Wang, Minghui, Wang, Jia, Wang, Xiaodong, Platzer, Konrad, Donkervoort, Sandra, Bönnemann, Carsten G., Wagner, Matias, Issa, Mahmoud Y., Elbendary, Hasnaa M., Stanley, Valentina, Maroofian, Reza, Gleeson, Joseph G., Zaki, Maha S., Senderek, Jan, and Pandey, Udai Bhan

Published
2021
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6. RINT1 deficiency disrupts lipid metabolism and underlies a complex hereditary spastic paraplegia

Author

Launay, Nathalie, primary, Ruiz, Montserrat, additional, Planas-Serra, Laura, additional, Verdura, Edgard, additional, Rodríguez-Palmero, Agustí, additional, Schlüter, Agatha, additional, Goicoechea, Leire, additional, Guilera, Cristina, additional, Casas, Josefina, additional, Campelo, Felix, additional, Jouanguy, Emmanuelle, additional, Casanova, Jean-Laurent, additional, Boespflug-Tanguy, Odile, additional, Vazquez Cancela, Maria, additional, Gutiérrez-Solana, Luis González, additional, Casasnovas, Carlos, additional, Area-Gomez, Estela, additional, and Pujol, Aurora, additional

Published
2023
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7. RINT1 deficiency disrupts lipid metabolism and underlies a complex hereditary spastic paraplegia

Author

Ministerio de Ciencia e Innovación (España), Launay, Nathalie, Ruiz, Montserrat, Planas-Serra, Laura, Verdura, Edgard, Rodríguez-Palmero, Agustí, Schlüter, Agatha, Goicoechea, Leire, Guilera, Cristina, Casas, Josefina, Campelo, Felix, Jouanguy, Emmanuelle, Casanova, Jean-Laurent, Boespflug-Tanguy, Odile, Vazquez Cancela, Maria, Gutiérrez-Solana, Luis González, Casasnovas, Carlos, Area-Gomez, Estela, Pujol, Aurora, Ministerio de Ciencia e Innovación (España), Launay, Nathalie, Ruiz, Montserrat, Planas-Serra, Laura, Verdura, Edgard, Rodríguez-Palmero, Agustí, Schlüter, Agatha, Goicoechea, Leire, Guilera, Cristina, Casas, Josefina, Campelo, Felix, Jouanguy, Emmanuelle, Casanova, Jean-Laurent, Boespflug-Tanguy, Odile, Vazquez Cancela, Maria, Gutiérrez-Solana, Luis González, Casasnovas, Carlos, Area-Gomez, Estela, and Pujol, Aurora

Abstract

The Rad50 interacting protein 1 (Rint1) is a key player in vesicular trafficking between the ER and Golgi apparatus. Biallelic variants in RINT1 cause infantile-onset episodic acute liver failure (ALF). Here, we describe 3 individuals from 2 unrelated families with novel biallelic RINT1 loss-of-function variants who presented with early onset spastic paraplegia, ataxia, optic nerve hypoplasia, and dysmorphic features, broadening the previously described phenotype. Our functional and lipidomic analyses provided evidence that pathogenic RINT1 variants induce defective lipid-droplet biogenesis and profound lipid abnormalities in fibroblasts and plasma that impact both neutral lipid and phospholipid metabolism, including decreased triglycerides and diglycerides, phosphatidylcholine/phosphatidylserine ratios, and inhibited Lands cycle. Further, RINT1 mutations induced intracellular ROS production and reduced ATP synthesis, affecting mitochondria with membrane depolarization, aberrant cristae ultrastructure, and increased fission. Altogether, our results highlighted the pivotal role of RINT1 in lipid metabolism and mitochondria function, with a profound effect in central nervous system development.

Published
2023

9. Diagnosis of Genetic White Matter Disorders by Singleton Whole-Exome and Genome Sequencing Using Interactome-Driven Prioritization

Author

Schlüter, Agatha, Rodríguez-Palmero, Agustí, Verdura, Edgard, Vélez-Santamaría, Valentina, Ruiz, Montserrat, Fourcade, Stéphane, Planas-Serra, Laura, Martínez, Juan José, Guilera, Cristina, Girós, Marisa, Artuch, R, Yoldi, María Eugenia, O'Callaghan, Mar, García-Cazorla, Angels, Armstrong, Judith, Marti, Itxaso, Mondragón Rezola, Elisabet, Redin, Claire, Mandel, Jean Louis, Conejo, David, Sierra-Córcoles, Concepción, Beltrán, Sergi, Gut, Marta, Vázquez, Elida, del Toro, Mireia, Troncoso, Mónica, Pérez-Jurado, Luis Alberto, Gutiérrez-Solana, Luis G., López de Munain, Adolfo, Casasnovas, Carlos, Aguilera-Albesa, Sergio, Macaya Ruiz, Alfons, Pujol, Aurora, Universitat Autònoma de Barcelona, Schlüter, Agatha, Rodríguez-Palmero, Agustí, Verdura, Edgard, Vélez-Santamaría, Valentina, Ruiz, Montserrat, Fourcade, Stéphane, Planas-Serra, Laura, Martínez, Juan José, Guilera, Cristina, Girós, Marisa, Artuch, R, Yoldi, María Eugenia, O'Callaghan, Mar, García-Cazorla, Angels, Armstrong, Judith, Marti, Itxaso, Mondragón Rezola, Elisabet, Redin, Claire, Mandel, Jean Louis, Conejo, David, Sierra-Córcoles, Concepción, Beltrán, Sergi, Gut, Marta, Vázquez, Elida, del Toro, Mireia, Troncoso, Mónica, Pérez-Jurado, Luis Alberto, Gutiérrez-Solana, Luis G., López de Munain, Adolfo, Casasnovas, Carlos, Aguilera-Albesa, Sergio, Macaya Ruiz, Alfons, Pujol, Aurora, and Universitat Autònoma de Barcelona

Abstract

Genetic white matter disorders (GWMD) are of heterogeneous origin, with >100 causal genes identified to date. Classic targeted approaches achieve a molecular diagnosis in only half of all patients. We aimed to determine the clinical utility of singleton whole-exome sequencing and whole-genome sequencing (sWES-WGS) interpreted with a phenotype- and interactome-driven prioritization algorithm to diagnose GWMD while identifying novel phenotypes and candidate genes. A case series of patients of all ages with undiagnosed GWMD despite extensive standard-of-care paraclinical studies were recruited between April 2017 and December 2019 in a collaborative study at the Bellvitge Biomedical Research Institute (IDIBELL) and neurology units of tertiary Spanish hospitals. We ran sWES and WGS and applied our interactome-prioritization algorithm based on the network expansion of a seed group of GWMD-related genes derived from the Human Phenotype Ontology terms of each patient. We evaluated 126 patients (101 children and 25 adults) with ages ranging from 1 month to 74 years. We obtained a first molecular diagnosis by singleton WES in 59% of cases, which increased to 68% after annual reanalysis, and reached 72% after WGS was performed in 16 of the remaining negative cases. We identified variants in 57 different genes among 91 diagnosed cases, with the most frequent being RNASEH2B, EIF2B5, POLR3A, and PLP1, and a dual diagnosis underlying complex phenotypes in 6 families, underscoring the importance of genomic analysis to solve these cases. We discovered 9 candidate genes causing novel diseases and propose additional putative novel candidate genes for yet-to-be discovered GWMD. Our strategy enables a high diagnostic yield and is a good alternative to trio WES/WGS for GWMD. It shortens the time to diagnosis compared to the classical targeted approach, thus optimizing appropriate management. Furthermore, the interactome-driven prioritization pipeline enables the discovery of novel diseas

Published
2022

10. Systematic Collaborative Reanalysis of Genomic Data Improves Diagnostic Yield in Neurologic Rare Diseases

Author

Bullich, Gemma, primary, Matalonga, Leslie, additional, Pujadas, Montserrat, additional, Papakonstantinou, Anastasios, additional, Piscia, Davide, additional, Tonda, Raúl, additional, Artuch, Rafael, additional, Gallano, Pia, additional, Garrabou, Glòria, additional, González, Juan R., additional, Grinberg, Daniel, additional, Guitart, Míriam, additional, Laurie, Steven, additional, Lázaro, Conxi, additional, Luengo, Cristina, additional, Martí, Ramon, additional, Milà, Montserrat, additional, Ovelleiro, David, additional, Parra, Genís, additional, Pujol, Aurora, additional, Tizzano, Eduardo, additional, Macaya, Alfons, additional, Palau, Francesc, additional, Ribes, Antònia, additional, Pérez-Jurado, Luis A., additional, Beltran, Sergi, additional, Schlüter, Agatha, additional, Rodriguez-Palmero, Agustí, additional, Cáceres, Alejandro, additional, Nascimento, Andrés, additional, García-Cazorla, Àngels, additional, Cueto-González, Anna, additional, Marcé-Grau, Anna, additional, Nel.lo, Anna Ruiz, additional, Martínez-Monseny, Antonio, additional, Sànchez, Aurora, additional, García, Belén, additional, Pérez-Dueñas, Belén, additional, Gel, Bernat, additional, Fusté, Berta, additional, Hernández-Ferrer, Carles, additional, Casasnovas, Carlos, additional, Ortez, Carlos, additional, Arjona, César, additional, Hernando-Davalillo, Cristina, additional, de Benito, Daniel Natera, additional, Amador, Daniel Picó, additional, Gómez-Andrés, David, additional, Yubero, Dèlia, additional, Pelegrí-Sisó, Dolors, additional, Verdura, Edgard, additional, García-Arumí, Elena, additional, Castellanos, Elisabeth, additional, Gabau, Elisabeth, additional, Tobías, Ester, additional, López-Grondona, Fermina, additional, Cardellach, Francesc, additional, Garcia-Garcia, Francesc Josep, additional, Munell, Francina, additional, Tort, Frederic, additional, Aznar, Gemma, additional, Olivé-Cirera, Gemma, additional, Tell, Gemma, additional, Muñoz-Pujol, Gerard, additional, Paramonov, Ida, additional, Blanco, Ignacio, additional, Madrigal, Irene, additional, Valenzuela, Irene, additional, Gut, Ivo, additional, Cusco, Ivon, additional, Trotta, Jean-Rémi, additional, Cruz, Jordi, additional, Díaz-Manera, Jordi, additional, Milisenda, José César, additional, Ma Grau, Josep, additional, Garcia-Villoria, Judit, additional, Armstrong, Judith, additional, Cantó, Judith, additional, Sala-Coromina, Júlia, additional, Rodríguez-Revenga, Laia, additional, Alias, Laura, additional, Gort, Laura, additional, González-Quereda, Lídia, additional, Costa, Mar, additional, Fernández-Callejo, Marcos, additional, López-Sánchez, Marcos, additional, Álvarez-Mora, Maria Isabel, additional, Gut, Marta, additional, Serrano, Mercedes, additional, Raspall-Chaure, Miquel, additional, Toro, Mireia del, additional, Bayés, Mònica, additional, Díez, Neus Baena, additional, Spataro, Nino, additional, Capdevila, Núria, additional, Ugarteburu, Olatz, additional, Muñoz-Cabello, Patricia, additional, Duque, Penélope Romero, additional, Rabionet, Raquel, additional, Rojas-García, Ricard, additional, Calvo, Rosa, additional, Urreizti, Roser, additional, Bernal, Sara, additional, Boronat, Susana, additional, Balcells, Susanna, additional, and Vendrell, Teresa, additional

Published
2022
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11. Biallelic variants in SLC35B2 cause a novel chondrodysplasia with hypomyelinating leukodystrophy

Author

Guasto, Alessandra, primary, Dubail, Johanne, additional, Aguilera-Albesa, Sergio, additional, Paganini, Chiara, additional, Vanhulle, Catherine, additional, Haouari, Walid, additional, Gorría-Redondo, Nerea, additional, Aznal-Sainz, Elena, additional, Boddaert, Nathalie, additional, Planas-Serra, Laura, additional, Schlüter, Agatha, additional, Vélez-Santamaría, Valentina, additional, Verdura, Edgard, additional, Bruneel, Arnaud, additional, Rossi, Antonio, additional, Huber, Céline, additional, Pujol, Aurora, additional, and Cormier-Daire, Valérie, additional

Published
2022
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12. Diagnosis of Genetic White Matter Disorders by Singleton Whole-Exome and Genome Sequencing Using Interactome-Driven Prioritization

Author

Schlüter, Agatha, primary, Rodríguez-Palmero, Agustí, additional, Verdura, Edgard, additional, Vélez-Santamaría, Valentina, additional, Ruiz, Montserrat, additional, Fourcade, Stéphane, additional, Planas-Serra, Laura, additional, Martínez, Juan José, additional, Guilera, Cristina, additional, Girós, Marisa, additional, Artuch, Rafael, additional, Yoldi, María Eugenia, additional, O'Callaghan, Mar, additional, García-Cazorla, Angels, additional, Armstrong, Judith, additional, Marti, Itxaso, additional, Mondragón Rezola, Elisabet, additional, Redin, Claire, additional, Mandel, Jean Louis, additional, Conejo, David, additional, Sierra-Córcoles, Concepción, additional, Beltrán, Sergi, additional, Gut, Marta, additional, Vázquez, Elida, additional, del Toro, Mireia, additional, Troncoso, Mónica, additional, Pérez-Jurado, Luis A., additional, Gutiérrez-Solana, Luis G., additional, López de Munain, Adolfo, additional, Casasnovas, Carlos, additional, Aguilera-Albesa, Sergio, additional, Macaya, Alfons, additional, and Pujol, Aurora, additional

Published
2022
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13. Bi-allelic variants in the mitochondrial RNase P subunit PRORP cause mitochondrial tRNA processing defects and pleiotropic multisystem presentations

Author

Hochberg, Irit, primary, Demain, Leigh A.M., additional, Richer, Julie, additional, Thompson, Kyle, additional, Urquhart, Jill E., additional, Rea, Alessandro, additional, Pagarkar, Waheeda, additional, Rodríguez-Palmero, Agustí, additional, Schlüter, Agatha, additional, Verdura, Edgard, additional, Pujol, Aurora, additional, Quijada-Fraile, Pilar, additional, Amberger, Albert, additional, Deutschmann, Andrea J., additional, Demetz, Sandra, additional, Gillespie, Meredith, additional, Belyantseva, Inna A., additional, McMillan, Hugh J., additional, Barzik, Melanie, additional, Beaman, Glenda M., additional, Motha, Reeya, additional, Ng, Kah Ying, additional, O’Sullivan, James, additional, Williams, Simon G., additional, Bhaskar, Sanjeev S., additional, Lawrence, Isabella R., additional, Jenkinson, Emma M., additional, Zambonin, Jessica L., additional, Blumenfeld, Zeev, additional, Yalonetsky, Sergey, additional, Oerum, Stephanie, additional, Rossmanith, Walter, additional, Yue, Wyatt W., additional, Zschocke, Johannes, additional, Munro, Kevin J., additional, Battersby, Brendan J., additional, Friedman, Thomas B., additional, Taylor, Robert W., additional, O’Keefe, Raymond T., additional, and Newman, William G., additional

Published
2021
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16. Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy

Author

Verdura, Edgard, primary, Rodríguez-Palmero, Agustí, additional, Vélez-Santamaria, Valentina, additional, Planas-Serra, Laura, additional, de la Calle, Irene, additional, Raspall-Chaure, Miquel, additional, Roubertie, Agathe, additional, Benkirane, Mehdi, additional, Saettini, Francesco, additional, Pavinato, Lisa, additional, Mandrile, Giorgia, additional, O’Leary, Melanie, additional, O’Heir, Emily, additional, Barredo, Estibaliz, additional, Chacón, Almudena, additional, Michaud, Vincent, additional, Goizet, Cyril, additional, Ruiz, Montserrat, additional, Schlüter, Agatha, additional, Rouvet, Isabelle, additional, Sala-Coromina, Julia, additional, Fossati, Chiara, additional, Iascone, Maria, additional, Canonico, Francesco, additional, Marcé-Grau, Anna, additional, de Souza, Precilla, additional, Adams, David R, additional, Casasnovas, Carlos, additional, Rehm, Heidi L, additional, Mefford, Heather C, additional, González Gutierrez-Solana, Luis, additional, Brusco, Alfredo, additional, Koenig, Michel, additional, Macaya, Alfons, additional, and Pujol, Aurora, additional

Published
2021
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17. Bi-allelic variants in the mitochondrial RNase P subunit PRORP cause mitochondrial tRNA processing defects and pleiotropic multisystem presentations

Author

Hochberg, Irit, Demain, Leigh A.M., Richer, Julie, Thompson, Kyle, Urquhart, Jill E., Rea, Alessandro, Pagarkar, Waheeda, Rodríguez-Palmero, Agustí, Schlüter, Agatha, Verdura, Edgard, Pujol, Aurora, Quijada-Fraile, Pilar, Amberger, Albert, Deutschmann, Andrea J., Demetz, Sandra, Gillespie, Meredith, Belyantseva, Inna A., McMillan, Hugh J., Barzik, Melanie, Beaman, Glenda M., Motha, Reeya, Ng, Kah Ying, O'Sullivan, James, Williams, Simon G., Bhaskar, Sanjeev S., Lawrence, Isabella R., Jenkinson, Emma M., Zambonin, Jessica L., Blumenfeld, Zeev, Yalonetsky, Sergey, Oerum, Stephanie, Rossmanith, Walter, Yue, Wyatt W., Zschocke, Johannes, Munro, Kevin J., Battersby, Brendan J., Friedman, Thomas B., Taylor, Robert W., O'Keefe, Raymond T., Newman, William G., Hochberg, Irit, Demain, Leigh A.M., Richer, Julie, Thompson, Kyle, Urquhart, Jill E., Rea, Alessandro, Pagarkar, Waheeda, Rodríguez-Palmero, Agustí, Schlüter, Agatha, Verdura, Edgard, Pujol, Aurora, Quijada-Fraile, Pilar, Amberger, Albert, Deutschmann, Andrea J., Demetz, Sandra, Gillespie, Meredith, Belyantseva, Inna A., McMillan, Hugh J., Barzik, Melanie, Beaman, Glenda M., Motha, Reeya, Ng, Kah Ying, O'Sullivan, James, Williams, Simon G., Bhaskar, Sanjeev S., Lawrence, Isabella R., Jenkinson, Emma M., Zambonin, Jessica L., Blumenfeld, Zeev, Yalonetsky, Sergey, Oerum, Stephanie, Rossmanith, Walter, Yue, Wyatt W., Zschocke, Johannes, Munro, Kevin J., Battersby, Brendan J., Friedman, Thomas B., Taylor, Robert W., O'Keefe, Raymond T., and Newman, William G.

Abstract

Human mitochondrial RNase P (mt-RNase P) is responsible for 5' end processing of mitochondrial precursor tRNAs, a vital step in mitochondrial RNA maturation, and is comprised of three protein subunits: TRMT10C, SDR5C1 (HSD10), and PRORP. Pathogenic variants in TRMT10C and SDR5C1 are associated with distinct recessive or x-linked infantile onset disorders, resulting from defects in mitochondrial RNA processing. We report four unrelated families with multisystem disease associated with bi-allelic variants in PRORP, the metallonuclease subunit of mt-RNase P. Affected individuals presented with variable phenotypes comprising sensorineural hearing loss, primary ovarian insufficiency, developmental delay, and brain white matter changes. Fibroblasts from affected individuals in two families demonstrated decreased steady state levels of PRORP, an accumulation of unprocessed mitochondrial transcripts, and decreased steady state levels of mitochondrial-encoded proteins, which were rescued by introduction of the wild-type PRORP cDNA. In mt-tRNA processing assays performed with recombinant mt-RNase P proteins, the disease-associated variants resulted in diminished mitochondrial tRNA processing. Identification of disease-causing variants in PRORP indicates that pathogenic variants in all three subunits of mt-RNase P can cause mitochondrial dysfunction, each with distinct pleiotropic clinical presentations.

Published
2021

18. DLG4-related synaptopathy:a new rare brain disorder

Author

Rodríguez-Palmero, Agustí, Boerrigter, Melissa Maria, Gómez-Andrés, David, Aldinger, Kimberly A., Marcos-Alcalde, Íñigo, Popp, Bernt, Everman, David B., Lovgren, Alysia Kern, Arpin, Stephanie, Bahrambeigi, Vahid, Beunders, Gea, Bisgaard, Anne Marie, Bjerregaard, V. A., Bruel, Ange Line, Challman, Thomas D., Cogné, Benjamin, Coubes, Christine, de Man, Stella A., Denommé-Pichon, Anne Sophie, Dye, Thomas J., Elmslie, Frances, Feuk, Lars, García-Miñaúr, Sixto, Gertler, Tracy, Giorgio, Elisa, Gruchy, Nicolas, Haack, Tobias B., Haldeman-Englert, Chad R., Haukanes, Bjørn Ivar, Hoyer, Juliane, Hurst, Anna C.E., Isidor, Bertrand, Soller, Maria Johansson, Kushary, Sulagna, Kvarnung, Malin, Landau, Yuval E., Leppig, Kathleen A., Lindstrand, Anna, Kleinendorst, Lotte, MacKenzie, Alex, Mandrile, Giorgia, Mendelsohn, Bryce A., Moghadasi, Setareh, Morton, Jenny E., Moutton, Sebastien, Müller, Amelie J., O’Leary, Melanie, Pacio-Míguez, Marta, Palomares-Bralo, Maria, Parikh, Sumit, Pfundt, Rolph, Pode-Shakked, Ben, Rauch, Anita, Repnikova, Elena, Revah-Politi, Anya, Ross, Meredith J., Ruivenkamp, Claudia A.L., Sarrazin, Elisabeth, Savatt, Juliann M., Schlüter, Agatha, Schönewolf-Greulich, Bitten, Shad, Zohra, Shaw-Smith, Charles, Shieh, Joseph T., Shohat, Motti, Spranger, Stephanie, Thiese, Heidi, Mau-Them, Frederic Tran, van Bon, Bregje, van de Burgt, Ineke, van de Laar, Ingrid M.B.H., van Drie, Esmée, van Haelst, Mieke M., van Ravenswaaij-Arts, Conny M., Verdura, Edgard, Vitobello, Antonio, Waldmüller, Stephan, Whiting, Sharon, Zweier, Christiane, Prada, Carlos E., de Vries, Bert B.A., Dobyns, William B., Reiter, Simone F., Gómez-Puertas, Paulino, Pujol, Aurora, Tümer, Zeynep, Rodríguez-Palmero, Agustí, Boerrigter, Melissa Maria, Gómez-Andrés, David, Aldinger, Kimberly A., Marcos-Alcalde, Íñigo, Popp, Bernt, Everman, David B., Lovgren, Alysia Kern, Arpin, Stephanie, Bahrambeigi, Vahid, Beunders, Gea, Bisgaard, Anne Marie, Bjerregaard, V. A., Bruel, Ange Line, Challman, Thomas D., Cogné, Benjamin, Coubes, Christine, de Man, Stella A., Denommé-Pichon, Anne Sophie, Dye, Thomas J., Elmslie, Frances, Feuk, Lars, García-Miñaúr, Sixto, Gertler, Tracy, Giorgio, Elisa, Gruchy, Nicolas, Haack, Tobias B., Haldeman-Englert, Chad R., Haukanes, Bjørn Ivar, Hoyer, Juliane, Hurst, Anna C.E., Isidor, Bertrand, Soller, Maria Johansson, Kushary, Sulagna, Kvarnung, Malin, Landau, Yuval E., Leppig, Kathleen A., Lindstrand, Anna, Kleinendorst, Lotte, MacKenzie, Alex, Mandrile, Giorgia, Mendelsohn, Bryce A., Moghadasi, Setareh, Morton, Jenny E., Moutton, Sebastien, Müller, Amelie J., O’Leary, Melanie, Pacio-Míguez, Marta, Palomares-Bralo, Maria, Parikh, Sumit, Pfundt, Rolph, Pode-Shakked, Ben, Rauch, Anita, Repnikova, Elena, Revah-Politi, Anya, Ross, Meredith J., Ruivenkamp, Claudia A.L., Sarrazin, Elisabeth, Savatt, Juliann M., Schlüter, Agatha, Schönewolf-Greulich, Bitten, Shad, Zohra, Shaw-Smith, Charles, Shieh, Joseph T., Shohat, Motti, Spranger, Stephanie, Thiese, Heidi, Mau-Them, Frederic Tran, van Bon, Bregje, van de Burgt, Ineke, van de Laar, Ingrid M.B.H., van Drie, Esmée, van Haelst, Mieke M., van Ravenswaaij-Arts, Conny M., Verdura, Edgard, Vitobello, Antonio, Waldmüller, Stephan, Whiting, Sharon, Zweier, Christiane, Prada, Carlos E., de Vries, Bert B.A., Dobyns, William B., Reiter, Simone F., Gómez-Puertas, Paulino, Pujol, Aurora, and Tümer, Zeynep

Abstract

Purpose: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants. Methods: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing. Results: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit–hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies. Conclusion: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy. [Figure not available: see fulltext.]

Published
2021

19. A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases

Author

Neurociencias, Neurozientziak, Verdura, Edgard, Schlüter, Agatha, Fernández Eulate, Gorka, Ramos Martín, Raquel, Zulaica, Miren, Planas Serra, Laura, Ruiz, Montserrat, Fourcade, Stéphane, Casasnovas, Carlos, López de Munain Arregui, Adolfo José, Neurociencias, Neurozientziak, Verdura, Edgard, Schlüter, Agatha, Fernández Eulate, Gorka, Ramos Martín, Raquel, Zulaica, Miren, Planas Serra, Laura, Ruiz, Montserrat, Fourcade, Stéphane, Casasnovas, Carlos, and López de Munain Arregui, Adolfo José

Abstract

Objective To identify causative mutations in a patient affected by ataxia and spastic paraplegia. Methods Whole-exome sequencing (WES) and whole-genome sequencing (WGS) were performed using patient's DNA sample. RT-PCR and cDNA Sanger sequencing were performed on RNA extracted from patient's fibroblasts, as well as western blot. Results A novel missense variant in SPG7 (c.2195T> C; p.Leu732Pro) was first found by whole-exome sequencing (WES), while the second, also unreported, deep intronic variant (c.286 + 853A>G) was identified by whole-genome sequencing (WGS). RT-PCR confirmed the in silico predictions showing that this variant activated a cryptic splice site, inducing the inclusion of a pseudoexon into the mRNA sequence, which encoded a premature stop codon. Western blot showed decreased SPG7 levels in patient's fibroblasts. Interpretation Identification of a deep intronic variant in SPG7, which could only have been detected by performing WGS, led to a diagnosis in this HSP patient. This case challenges the notion of an autosomal dominant inheritance for SPG7, and illustrates the importance of performing WGS subsequently or alternatively to WES to find additional mutations, especially in patients carrying one variant in a gene causing a predominantly autosomal recessive disease.

Published
2020

20. A novel hypomorphic splice variant in EIF2B5 gene is associated with mild ovarioleukodystrophy

Author

Rodríguez-Palmero, Agustí, Schlüter, Agatha, Verdura, Edgard, Ruiz, Montserrat, Martínez, Juan José, Gourlaouen, Isabelle, Ka, Chandran, Lobato, Ricardo, Casasnovas, Carlos, Le Gac, Gérald, Fourcade, Stéphane, Pujol, Aurora, Rodríguez-Palmero, Agustí, Schlüter, Agatha, Verdura, Edgard, Ruiz, Montserrat, Martínez, Juan José, Gourlaouen, Isabelle, Ka, Chandran, Lobato, Ricardo, Casasnovas, Carlos, Le Gac, Gérald, Fourcade, Stéphane, and Pujol, Aurora

Abstract

To identify the genetic cause in an adult ovarioleukodystrophy patient resistant to diagnosis. We applied whole-exome sequencing (WES) to a vanishing white matter disease patient associated with premature ovarian failure at 26 years of age. We functionally tested an intronic variant by RT-PCR on patient's peripheral blood mononuclear cells (PBMC) and by minigene splicing assay. WES analysis identified two novel variants in the EIF2B5 gene: c.725A > G (p.Tyr242Cys) and an intronic noncanonical mutation (c.1156 + 13G>A). This intronic mutation resulted into generation of various isoforms both in patient's PBMC and in the minigene splicing assay, showing that ~20% residual wild-type isoform is still expressed by the intronic-mutated allele alone, concordant with an hypomorphic effect of this variant. We report two novel variants in EIF2B5, one of them a noncanonical intronic splice variant, located at a +13 intronic position. This position is mutated only in 0.05% of ClinVar intronic mutations described so far. Furthermore, we illustrate how minigene splicing assay may be advantageous when validating splice-altering variants, in this case highlighting the coexistence of wild-type and mutated forms, probably explaining this patient's milder, late-onset phenotype.

Published
2020

21. Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia

Author

Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica, Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III - European Regional Development Fund. ERDF, a way to build Europe, Instituto de Salud Carlos III (Miguel Servet programme - European Social Fund. ESF investing in your future), la Marato de TV3, Ministerio de Economia, Industria y Competividad (Juan de la Cierva programme), Secretariat for Universities and Research of the Ministry of Business and Knowledge of the Government of Catalonia, URDCat program, Verdura, Edgard, Fons, Carme, Schlüter, Agatha, Ruiz, Montserrat, Fourcade, Stéphane, Casasnovas, Carlos, Castellano Orozco, Antonio Gonzalo, Pujol, Aurora, Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica, Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III - European Regional Development Fund. ERDF, a way to build Europe, Instituto de Salud Carlos III (Miguel Servet programme - European Social Fund. ESF investing in your future), la Marato de TV3, Ministerio de Economia, Industria y Competividad (Juan de la Cierva programme), Secretariat for Universities and Research of the Ministry of Business and Knowledge of the Government of Catalonia, URDCat program, Verdura, Edgard, Fons, Carme, Schlüter, Agatha, Ruiz, Montserrat, Fourcade, Stéphane, Casasnovas, Carlos, Castellano Orozco, Antonio Gonzalo, and Pujol, Aurora

Abstract

Background: Since 1994, over 50 families affected by the episodic ataxia type 1 disease spectrum have been described with mutations in KCNA1, encoding the voltage-gated K+ channel subunit Kv1.1. All of these mutations are either transmitted in an autosomal-dominant mode or found as de novo events. Methods: A patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy was sequenced by whole-exome sequencing (WES). A candidate variant was tested using cellular assays and patch-clamp recordings. Results: WES revealed a homozygous variant (p.Val368Leu) in KCNA1, involving a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG). Functional analysis showed that mutant protein alone failed to produce functional channels in homozygous state, while coexpression with wild-type produced no effects on K+ currents, similar to wild-type protein alone. Treatment with oxcarbazepine, a sodium channel blocker, proved effective in controlling seizures. Conclusion: This newly identified variant is the first to be reported to act in a recessive mode of inheritance in KCNA1. These findings serve as a cautionary tale for the diagnosis of channelopathies, in which an unreported phenotypic presentation or mode of inheritance for the variant of interest can hinder the identification of causative variants and adequate treatment choice.

Published
2020

22. Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia

Author

Centro de Investigación Biomédica en Red Enfermedades Raras (España), Generalitat de Catalunya, Hesperia Foundation, Instituto de Salud Carlos III, European Commission, Fundació La Marató de TV3, Ministerio de Economía y Competitividad (España), Verdura, Edgard, Font, Carme, Schlüter, Agatha, Ruiz, Montserrat, Fourcade, Stéphane, Casasnovas, Carlos, Castellano, Antonio, Pujol, Aurora, Centro de Investigación Biomédica en Red Enfermedades Raras (España), Generalitat de Catalunya, Hesperia Foundation, Instituto de Salud Carlos III, European Commission, Fundació La Marató de TV3, Ministerio de Economía y Competitividad (España), Verdura, Edgard, Font, Carme, Schlüter, Agatha, Ruiz, Montserrat, Fourcade, Stéphane, Casasnovas, Carlos, Castellano, Antonio, and Pujol, Aurora

Abstract

[Background] Since 1994, over 50 families affected by the episodic ataxia type 1 disease spectrum have been described with mutations in KCNA1, encoding the voltage-gated K+ channel subunit Kv1.1. All of these mutations are either transmitted in an autosomal-dominant mode or found as de novo events., [Methods] A patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy was sequenced by whole-exome sequencing (WES). A candidate variant was tested using cellular assays and patch-clamp recordings., [Results] WES revealed a homozygous variant (p.Val368Leu) in KCNA1, involving a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG). Functional analysis showed that mutant protein alone failed to produce functional channels in homozygous state, while coexpression with wild-type produced no effects on K+ currents, similar to wild-type protein alone. Treatment with oxcarbazepine, a sodium channel blocker, proved effective in controlling seizures., [Conclusion] This newly identified variant is the first to be reported to act in a recessive mode of inheritance in KCNA1. These findings serve as a cautionary tale for the diagnosis of channelopathies, in which an unreported phenotypic presentation or mode of inheritance for the variant of interest can hinder the identification of causative variants and adequate treatment choice.

Published
2020

23. Expanding the clinical and genetic spectrum of PCYT2-related disorders

Author

Vélez-Santamaría, Valentina, primary, Verdura, Edgard, additional, Macmurdo, Colleen, additional, Planas-Serra, Laura, additional, Schlüter, Agatha, additional, Casas, Josefina, additional, Martínez, Juan José, additional, Casasnovas, Carlos, additional, Si, Yue, additional, Thompson, Stephanie S, additional, Maroofian, Reza, additional, and Pujol, Aurora, additional

Published
2020
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24. A novel hypomorphic splice variant in EIF2B5 gene is associated with mild ovarioleukodystrophy

Author

Rodríguez‐Palmero, Agustí, primary, Schlüter, Agatha, additional, Verdura, Edgard, additional, Ruiz, Montserrat, additional, Martínez, Juan José, additional, Gourlaouen, Isabelle, additional, Ka, Chandran, additional, Lobato, Ricardo, additional, Casasnovas, Carlos, additional, Le Gac, Gérald, additional, Fourcade, Stéphane, additional, and Pujol, Aurora, additional

Published
2020
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25. De novo mutations in the X-linked TFE3 gene cause intellectual disability with pigmentary mosaicism and storage disorder-like features

Author

Lehalle, Daphné, primary, Vabres, Pierre, additional, Sorlin, Arthur, additional, Bierhals, Tatjana, additional, Avila, Magali, additional, Carmignac, Virginie, additional, Chevarin, Martin, additional, Torti, Erin, additional, Abe, Yuichi, additional, Bartolomaeus, Tobias, additional, Clayton-Smith, Jill, additional, Cogné, Benjamin, additional, Cusco, Ivon, additional, Duplomb, Laurence, additional, De Bont, Eveline, additional, Duffourd, Yannis, additional, Duijkers, Floor, additional, Elpeleg, Orly, additional, Fattal, Aviva, additional, Geneviève, David, additional, Guillen Sacoto, Maria J, additional, Guimier, Anne, additional, Harris, David J, additional, Hempel, Maja, additional, Isidor, Bertrand, additional, Jouan, Thibaud, additional, Kuentz, Paul, additional, Koshimizu, Eriko, additional, Lichtenbelt, Klaske, additional, Loik Ramey, Valerie, additional, Maik, Miriam, additional, Miyakate, Sakoto, additional, Murakami, Yoshiko, additional, Pasquier, Laurent, additional, Pedro, Helio, additional, Simone, Laurie, additional, Sondergaard-Schatz, Krista, additional, St-Onge, Judith, additional, Thevenon, Julien, additional, Valenzuela, Irene, additional, Abou Jamra, Rami, additional, van Gassen, Koen, additional, van Haelst, Mieke M, additional, van Koningsbruggen, Silvana, additional, Verdura, Edgard, additional, Whelan Habela, Christa, additional, Zacher, Pia, additional, Rivière, Jean-Baptiste, additional, Thauvin-Robinet, Christel, additional, Betschinger, Joerg, additional, and Faivre, Laurence, additional

Published
2020
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26. A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases

Author

Verdura, Edgard, primary, Schlüter, Agatha, additional, Fernández‐Eulate, Gorka, additional, Ramos‐Martín, Raquel, additional, Zulaica, Miren, additional, Planas‐Serra, Laura, additional, Ruiz, Montserrat, additional, Fourcade, Stéphane, additional, Casasnovas, Carlos, additional, López de Munain, Adolfo, additional, and Pujol, Aurora, additional

Published
2019
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27. End‐Truncated LAMB1 Causes a Hippocampal Memory Defect and a Leukoencephalopathy.

Author

Aloui, Chaker, Hervé, Dominique, Marenne, Gaelle, Savenier, Florian, Le Guennec, Kilan, Bergametti, Francoise, Verdura, Edgard, Ludwig, Thomas E., Lebenberg, Jessica, Jabeur, Waliyde, Morel, Hélène, Coste, Thibault, Demarquay, Geneviève, Bachoumas, Panagiotis, Cogez, Julien, Mathey, Guillaume, Bernard, Emilien, Chabriat, Hugues, Génin, Emmanuelle, and Tournier‐Lasserve, Elisabeth

Subjects
MAGNETIC resonance imaging, CEREBRAL small vessel diseases, EXTRACELLULAR matrix proteins, LEUKOENCEPHALOPATHIES, HIPPOCAMPUS (Brain), CLINICAL medicine, EPISODIC memory
Abstract

Objective: The majority of patients with a familial cerebral small vessel disease (CSVD) referred for molecular screening do not show pathogenic variants in known genes. In this study, we aimed to identify novel CSVD causal genes. Methods: We performed a gene‐based collapsing test of rare protein‐truncating variants identified in exome data of 258 unrelated CSVD patients of an ethnically matched control cohort and of 2 publicly available large‐scale databases, gnomAD and TOPMed. Western blotting was used to investigate the functional consequences of variants. Clinical and magnetic resonance imaging features of mutated patients were characterized. Results: We showed that LAMB1 truncating variants escaping nonsense‐mediated messenger RNA decay are strongly overrepresented in CSVD patients, reaching genome‐wide significance (p < 5 × 10−8). Using 2 antibodies recognizing the N‐ and C‐terminal parts of LAMB1, we showed that truncated forms of LAMB1 are expressed in the endogenous fibroblasts of patients and trapped in the cytosol. These variants are associated with a novel phenotype characterized by the association of a hippocampal type episodic memory defect and a diffuse vascular leukoencephalopathy. Interpretation: These findings are important for diagnosis and clinical care, to avoid unnecessary and sometimes invasive investigations, and also from a mechanistic point of view to understand the role of extracellular matrix proteins in neuronal homeostasis. ANN NEUROL 2021;90:962–975 [ABSTRACT FROM AUTHOR]

Published
2021
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28. Altered tubulin detyrosination due to SVBP malfunction induces cytokinesis failure and senescence, underlying a complex hereditary spastic paraplegia.

Author

Launay, Nathalie, Espinosa‐Alcantud, Maria, Verdura, Edgard, Fernández‐Eulate, Gorka, Ondaro, Jon, Iruzubieta, Pablo, Marsal, Maria, Schlüter, Agatha, Ruiz, Montserrat, Fourcade, Stephane, Rodríguez‐Palmero, Agustí, Zulaica, Miren, Sistiaga, Andone, Labayru, Garazi, Loza‐Alvarez, Pablo, Vaquero, Alejandro, Lopez de Munain, Adolfo, and Pujol, Aurora

Subjects
*FAMILIAL spastic paraplegia, *MOTOR neuron diseases, *MONONUCLEAR leukocytes, *SPEECH apraxia, *CELLULAR aging
Abstract

Senescence, marked by permanent cell cycle arrest may contribute to the decline in regenerative potential and neuronal function, thereby promoting neurodegenerative disorders. In this study, we employed whole exome sequencing to identify a previously unreported biallelic missense variant in SVBP (p.Leu49Pro) in six patients from three unrelated families. These affected individuals present with a complex hereditary spastic paraplegia (HSP), peripheral neuropathy, verbal apraxia, and intellectual disability, exhibiting a milder phenotype compared to patients with nonsense SVBP mutations described previously. Consistent with SVBP's primary role as a chaperone necessary for VASH‐mediated tubulin detyrosination, both patient fibroblasts with the p.Leu49Pro mutation, and HeLa cells harboring an SVBP knockdown exhibit microtubule dynamic instability and alterations in pericentriolar material (PCM) component trafficking and centrosome cohesion. In patient fibroblasts, structural abnormalities in the centrosome trigger mitotic errors and cellular senescence. Notably, premature senescence characterized by elevated levels of p16INK4, was also observed in patient peripheral blood mononuclear cells (PBMCs). Taken together, our findings underscore the critical role of SVBP in the development and maintenance of the central nervous system, providing novel insights associating cytokinesis failure with cortical motor neuron disease and intellectual disability. [ABSTRACT FROM AUTHOR]

Published
2024
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29. Prognostic value of X-chromosome inactivation in symptomatic female carriers of dystrophinopathy

Author

Juan-Mateu Jonàs, Rodríguez Maria, Nascimento Andrés, Jiménez-Mallebrera Cecilia, González-Quereda Lidia, Rivas Eloy, Paradas Carmen, Madruga Marcos, Sánchez-Ayaso Pedro, Jou Cristina, González-Mera Laura, Munell Francina, Roig-Quilis Manuel, Rabasa Maria, Hernández-Lain Aurelio, Díaz-Manera Jorge, Gallardo Eduard, Pascual Jordi, Verdura Edgard, Colomer Jaume, Baiget Montserrat, Olivé Montse, and Gallano Pia

Subjects
Dystrophin, DMD, Symptomatic carrier, Duchenne muscular dystrophy, Becker muscular dystrophy, X-chromosome inactivation, Medicine
Abstract

Abstract Background Between 8% and 22% of female carriers of DMD mutations exhibit clinical symptoms of variable severity. Development of symptoms in DMD mutation carriers without chromosomal rearrangements has been attributed to skewed X-chromosome inactivation (XCI) favouring predominant expression of the DMD mutant allele. However the prognostic use of XCI analysis is controversial. We aimed to evaluate the correlation between X-chromosome inactivation and development of clinical symptoms in a series of symptomatic female carriers of dystrophinopathy. Methods We reviewed the clinical, pathological and genetic features of twenty-four symptomatic carriers covering a wide spectrum of clinical phenotypes. DMD gene analysis was performed using MLPA and whole gene sequencing in blood DNA and muscle cDNA. Blood and muscle DNA was used for X-chromosome inactivation (XCI) analysis thought the AR methylation assay in symptomatic carriers and their female relatives, asymptomatic carriers as well as non-carrier females. Results Symptomatic carriers exhibited 49.2% more skewed XCI profiles than asymptomatic carriers. The extent of XCI skewing in blood tended to increase in line with the severity of muscle symptoms. Skewed XCI patterns were found in at least one first-degree female relative in 78.6% of symptomatic carrier families. No mutations altering XCI in the XIST gene promoter were found. Conclusions Skewed XCI is in many cases familial inherited. The extent of XCI skewing is related to phenotype severity. However, the assessment of XCI by means of the AR methylation assay has a poor prognostic value, probably because the methylation status of the AR gene in muscle may not reflect in all cases the methylation status of the DMD gene.

Published
2012
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32. Impairment of the mitochondrial one-carbon metabolism enzyme SHMT2 causes a novel brain and heart developmental syndrome.

Author

García-Cazorla, Àngels, Verdura, Edgard, Juliá-Palacios, Natalia, Anderson, Eric N., Goicoechea, Leire, Planas-Serra, Laura, Tsogtbaatar, Enkhtuul, Dsouza, Nikita R., Schlüter, Agatha, Urreizti, Roser, Tarnowski, Jessica M., Gavrilova, Ralitza H., SHMT2 Working Group, Oyarzábal, Alfonso, Medina, Inés, Ormazábal, Aida, Muchart, Jordi, Carretero, Juan Manuel, Jou, Cristina, and del Toro, Mireia

Subjects
*ENZYME metabolism, *EYELASHES, *LIPS, *AMINO acid metabolism
Abstract

Keywords: SHMT2; Mitochondrial one-carbon metabolism; Congenital microcephaly; Perisylvian polymicrogyria; Cardiomyopathy EN SHMT2 Mitochondrial one-carbon metabolism Congenital microcephaly Perisylvian polymicrogyria Cardiomyopathy 971 975 5 11/17/20 20201201 NES 201201 The members of SHMT2 Working Group are listed in the Acknowledgements section. SHMT2 performs the first step in a series of reactions that provide one-carbon units covalently bound to folate species in mitochondria: it transfers one-carbon units from serine to tetrahydrofolate (THF), generating glycine and 5,10-methylene-THF [[4], [11]]. Microcephaly associated with hypomyelination is also seen in patients with loss of PYCR2, an enzyme of proline synthesis which interacts with SHMT2, causing hyperglycinemia, underscoring the impact of dysregulated glycine/serine levels on neurodevelopment [[6]]. [Extracted from the article]

Published
2020
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33. Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia.

Author

Verdura, Edgard, Fons, Carme, Schlüter, Agatha, Ruiz, Montserrat, Fourcade, Stéphane, Casasnovas, Carlos, Castellano, Antonio, and Pujol, Aurora

Abstract

Background Since 1994, over 50 families affected by the episodic ataxia type 1 disease spectrum have been described with mutations in KCNA1, encoding the voltage-gated K+ channel subunit Kv1.1. All of these mutations are either transmitted in an autosomal-dominant mode or found as de novo events. Methods A patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy was sequenced by whole-exome sequencing (WES). A candidate variant was tested using cellular assays and patch-clamp recordings. Results WES revealed a homozygous variant (p.Val368Leu) in KCNA1, involving a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG). Functional analysis showed that mutant protein alone failed to produce functional channels in homozygous state, while coexpression with wild-type produced no effects on K+ currents, similar to wild-type protein alone. Treatment with oxcarbazepine, a sodium channel blocker, proved effective in controlling seizures. Conclusion This newly identified variant is the first to be reported to act in a recessive mode of inheritance in KCNA1. These findings serve as a cautionary tale for the diagnosis of channelopathies, in which an unreported phenotypic presentation or mode of inheritance for the variant of interest can hinder the identification of causative variants and adequate treatment choice. [ABSTRACT FROM AUTHOR]

Published
2020
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34. A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases.

Author

Verdura, Edgard, Schlüter, Agatha, Fernández‐Eulate, Gorka, Ramos‐Martín, Raquel, Zulaica, Miren, Planas‐Serra, Laura, Ruiz, Montserrat, Fourcade, Stéphane, Casasnovas, Carlos, López de Munain, Adolfo, and Pujol, Aurora

Subjects
*FAMILIAL spastic paraplegia, *SCHOENLEIN-Henoch purpura, *WESTERN immunoblotting, *ANTISENSE DNA
Abstract

Objective: To identify causative mutations in a patient affected by ataxia and spastic paraplegia. Methods: Whole‐exome sequencing (WES) and whole‐genome sequencing (WGS) were performed using patient's DNA sample. RT‐PCR and cDNA Sanger sequencing were performed on RNA extracted from patient's fibroblasts, as well as western blot. Results: A novel missense variant in SPG7 (c.2195T> C; p.Leu732Pro) was first found by whole‐exome sequencing (WES), while the second, also unreported, deep intronic variant (c.286 + 853A>G) was identified by whole‐genome sequencing (WGS). RT‐PCR confirmed the in silico predictions showing that this variant activated a cryptic splice site, inducing the inclusion of a pseudoexon into the mRNA sequence, which encoded a premature stop codon. Western blot showed decreased SPG7 levels in patient's fibroblasts. Interpretation: Identification of a deep intronic variant in SPG7, which could only have been detected by performing WGS, led to a diagnosis in this HSP patient. This case challenges the notion of an autosomal dominant inheritance for SPG7, and illustrates the importance of performing WGS subsequently or alternatively to WES to find additional mutations, especially in patients carrying one variant in a gene causing a predominantly autosomal recessive disease. [ABSTRACT FROM AUTHOR]

Published
2020
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35. De novomutations in the X-linked TFE3gene cause intellectual disability with pigmentary mosaicism and storage disorder-like features

Author

Lehalle, Daphné, Vabres, Pierre, Sorlin, Arthur, Bierhals, Tatjana, Avila, Magali, Carmignac, Virginie, Chevarin, Martin, Torti, Erin, Abe, Yuichi, Bartolomaeus, Tobias, Clayton-Smith, Jill, Cogné, Benjamin, Cusco, Ivon, Duplomb, Laurence, De Bont, Eveline, Duffourd, Yannis, Duijkers, Floor, Elpeleg, Orly, Fattal, Aviva, Geneviève, David, Guillen Sacoto, Maria J, Guimier, Anne, Harris, David J, Hempel, Maja, Isidor, Bertrand, Jouan, Thibaud, Kuentz, Paul, Koshimizu, Eriko, Lichtenbelt, Klaske, Loik Ramey, Valerie, Maik, Miriam, Miyakate, Sakoto, Murakami, Yoshiko, Pasquier, Laurent, Pedro, Helio, Simone, Laurie, Sondergaard-Schatz, Krista, St-Onge, Judith, Thevenon, Julien, Valenzuela, Irene, Abou Jamra, Rami, van Gassen, Koen, van Haelst, Mieke M, van Koningsbruggen, Silvana, Verdura, Edgard, Whelan Habela, Christa, Zacher, Pia, Rivière, Jean-Baptiste, Thauvin-Robinet, Christel, Betschinger, Joerg, and Faivre, Laurence

Abstract

IntroductionPigmentary mosaicism (PM) manifests by pigmentation anomalies along Blaschko’s lines and represents a clue toward the molecular diagnosis of syndromic intellectual disability (ID). Together with new insights on the role for lysosomal signalling in embryonic stem cell differentiation, mutations in the X-linked transcription factor 3 (TFE3) have recently been reported in five patients. Functional analysis suggested these mutations to result in ectopic nuclear gain of functions.Materials and methodsSubsequent data sharing allowed the clustering of de novo TFE3variants identified by exome sequencing on DNA extracted from leucocytes in patients referred for syndromic ID with or without PM.ResultsWe describe the detailed clinical and molecular data of 17 individuals harbouring a de novo TFE3variant, including the patients that initially allowed reporting TFE3as a new disease-causing gene. The 12 females and 5 males presented with pigmentation anomalies on Blaschko’s lines, severe ID, epilepsy, storage disorder-like features, growth retardation and recognisable facial dysmorphism. The variant was at a mosaic state in at least two male patients. All variants were missense except one splice variant. Eleven of the 13 variants were localised in exon 4, 2 in exon 3, and 3 were recurrent variants.ConclusionThis series further delineates the specific storage disorder-like phenotype with PM ascribed to de novo TFE3mutation in exons 3 and 4. It confirms the identification of a novel X-linked human condition associated with mosaicism and dysregulation within the mechanistic target of rapamycin (mTOR) pathway, as well as a link between lysosomal signalling and human development.

Published
2020
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36. Disruption of a miR‐29 binding site leading to COL4A1 upregulation causes pontine autosomal dominant microangiopathy with leukoencephalopathy

Author

Verdura, Edgard, primary, Hervé, Dominique, additional, Bergametti, Françoise, additional, Jacquet, Clémence, additional, Morvan, Typhaine, additional, Prieto‐Morin, Carol, additional, Mackowiak, Alexandre, additional, Manchon, Eric, additional, Hosseini, Hassan, additional, Cordonnier, Charlotte, additional, Girard‐Buttaz, Isabelle, additional, Rosenstingl, Sophie, additional, Hagel, Christian, additional, Kuhlenbaümer, Gregor, additional, Leca‐Radu, Elena, additional, Goux, Didier, additional, Fleming, Lauren, additional, Van Agtmael, Tom, additional, Chabriat, Hugues, additional, Chapon, Françoise, additional, and Tournier‐Lasserve, Elisabeth, additional

Published
2016
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37. A novel mutation in the GFAPgene expands the phenotype of Alexander disease

Author

Casasnovas, Carlos, Verdura, Edgard, Vélez, Valentina, Schlu¨ter, Agatha, Pons-Escoda, Albert, Homedes, Christian, Ruiz, Montserrat, Fourcade, Stéphane, Launay, Nathalie, and Pujol, Aurora

Abstract

BackgroundAlexander disease, an autosomal dominant leukodystrophy, is caused by missense mutations in GFAP. Although mostly diagnosed in children, associated with severe leukoencephalopathy, milder adult forms also exist.MethodsA family affected by adult-onset spastic paraplegia underwent neurological examination and cerebral MRI. Two patients were sequenced by whole exome sequencing (WES). A candidate variant was functionally tested in an astrocytoma cell line.ResultsThe novel variant in GFAP(Glial Fibrillary Acidic Protein) N-terminal head domain (p.Gly18Val) cosegregated in multiple relatives (LOD score: 2.7). All patients, even those with the mildest forms, showed characteristic signal changes or atrophy in the brainstem and spinal cord MRIs, and abnormal MRS. In vitro, this variant did not cause significant protein aggregation, in contrast to most Alexander disease mutations characterised so far. However, cell area analysis showed larger size, a feature previously described in patients and mouse models.ConclusionWe suggest that this variant causes variable expressivity and an attenuated phenotype of Alexander disease type II, probably associated with alternative pathogenic mechanisms, that is, astrocyte enlargement. GFAPanalysis should be considered in adult-onset neurological presentations with pyramidal and bulbar symptoms, in particular when characteristic findings, such as the tadpole sign, are present in MRI. WES is a powerful tool to diagnose atypical cases.

Published
2019
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40. HeterozygousHTRA1mutations are associated with autosomal dominant cerebral small vessel disease

Author

Verdura, Edgard, primary, Hervé, Dominique, additional, Scharrer, Eva, additional, Amador, Maria del Mar, additional, Guyant-Maréchal, Lucie, additional, Philippi, Anne, additional, Corlobé, Astrid, additional, Bergametti, Françoise, additional, Gazal, Steven, additional, Prieto-Morin, Carol, additional, Beaufort, Nathalie, additional, Le Bail, Benoit, additional, Viakhireva, Irina, additional, Dichgans, Martin, additional, Chabriat, Hugues, additional, Haffner, Christof, additional, and Tournier-Lasserve, Elisabeth, additional

Published
2015
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41. Interplay between DMD Point Mutations and Splicing Signals in Dystrophinopathy Phenotypes

Author

Juan-Mateu, Jonàs, primary, González-Quereda, Lidia, additional, Rodríguez, Maria José, additional, Verdura, Edgard, additional, Lázaro, Kira, additional, Jou, Cristina, additional, Nascimento, Andrés, additional, Jiménez-Mallebrera, Cecilia, additional, Colomer, Jaume, additional, Monges, Soledad, additional, Lubieniecki, Fabiana, additional, Foncuberta, Maria Eugenia, additional, Pascual-Pascual, Samuel Ignacio, additional, Molano, Jesús, additional, Baiget, Montserrat, additional, and Gallano, Pia, additional

Published
2013
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42. Can whole-exome sequencing data be used for linkage analysis?

Author

Gazal, Steven, Gosset, Simon, Verdura, Edgard, Bergametti, Françoise, Guey, Stéphanie, Babron, Marie-Claude, and Tournier-Lasserve, Elisabeth

Abstract

Whole-exome sequencing (WES) has become the strategy of choice to identify causal variants in monogenic disorders. However, the list of candidate variants can be quite large, including false positives generated by sequencing errors. To reduce this list of candidate variants to the most relevant ones, a cost-effective strategy would be to focus on regions of linkage identified through linkage analysis conducted with common polymorphisms present in WES data. However, the non-uniform exon coverage of the genome and the lack of knowledge on the power of this strategy have largely precluded its use so far. To compare the performance of linkage analysis conducted with WES and SNP chip data in different situations, we performed simulations on two pedigree structures with, respectively, a dominant and a recessive trait segregating. We found that the performance of the two sets of markers at excluding regions of the genome were very similar, and there was no real gain at using SNP chip data compared with using the common SNPs extracted from WES data. When analyzing the real WES data available for these two pedigrees, we found that the linkage information derived from the WES common polymorphisms was able to reduce by half the list of candidate variants identified by a simple filtering approach. Conducting linkage analysis with WES data available on pedigrees and excluding among the candidate variants those that fall in excluded linkage regions is thus a powerful and cost-effective strategy to reduce the number of false-positive candidate variants.

Published
2016
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43. Interplay between DMD Point Mutations and Splicing Signals in Dystrophinopathy Phenotypes.

Author

Juan-Mateu, Jonàs, González-Quereda, Lidia, Rodríguez, Maria José, Verdura, Edgard, Lázaro, Kira, Jou, Cristina, Nascimento, Andrés, Jiménez-Mallebrera, Cecilia, Colomer, Jaume, Monges, Soledad, Lubieniecki, Fabiana, Foncuberta, Maria Eugenia, Pascual-Pascual, Samuel Ignacio, Molano, Jesús, Baiget, Montserrat, and Gallano, Pia

Subjects
DUCHENNE muscular dystrophy, GENETIC mutation, RNA splicing, PHENOTYPES, CELLULAR signal transduction, EXONS (Genetics), BIOCHEMISTRY, MOLECULAR biology
Abstract

DMD nonsense and frameshift mutations lead to severe Duchenne muscular dystrophy while in-frame mutations lead to milder Becker muscular dystrophy. Exceptions are found in 10% of cases and the production of alternatively spliced transcripts is considered a key modifier of disease severity. Several exonic mutations have been shown to induce exon-skipping, while splice site mutations result in exon-skipping or activation of cryptic splice sites. However, factors determining the splicing pathway are still unclear. Point mutations provide valuable information regarding the regulation of pre-mRNA splicing and elements defining exon identity in the DMD gene. Here we provide a comprehensive analysis of 98 point mutations related to clinical phenotype and their effect on muscle mRNA and dystrophin expression. Aberrant splicing was found in 27 mutations due to alteration of splice sites or splicing regulatory elements. Bioinformatics analysis was performed to test the ability of the available algorithms to predict consequences on mRNA and to investigate the major factors that determine the splicing pathway in mutations affecting splicing signals. Our findings suggest that the splicing pathway is highly dependent on the interplay between splice site strength and density of regulatory elements. [ABSTRACT FROM AUTHOR]

Published
2013
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