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X chromosome inactivation does not necessarily determine the severity of the phenotype in Rett syndrome patients

2019; Nature Portfolio; Volume: 9; Issue: 1 Linguagem: Inglês

10.1038/s41598-019-48385-w

2045-2322

Clara Xiol, Silvia M. Vidal, Ainhoa Pascual‐Alonso, Laura Campello Blasco, Núria Brandi, Paola Pacheco, Edgar Gerotina, Mar O’Callaghan, Mercè Pineda, Judith Armstrong, Francisco Javier Aguirre, Montserrat Aleu, Xènia Alonso, Mercè Alsius, Maria Inmaculada Amorós, Guillermo Antiñolo, Lourdes Aquino, María del Carmen Arellano Gálvez, Gema Arriola, Rosa Arteaga, Neus Baena, Montserrat Barcos, Nuria Belzunces, Susana Boronat, Tomás Camacho, Jaume Campistol, Miguel Del Campo, Andrea Campo, Ramon Cancho, R Candau, Ignacio Canós, María del Carmen Carrascosa, Francisco Carratalá-Marco, Carmen Jovaní Casano, Pedro Castro, Ana María Cobo, J. Colomer, David Conejo, Maria José Corrales, Rocío Jiménez Cortés, Gabriel Cruz, Gábor Csányi, María Teresa de Santos, María de Toledo, Miguel Del Campo, Mireia del Toro, Rosario Domingo‐Jiménez, Anna Duat, Rosario Duque, Ana María Esparza, Rosa Fernández, Maria Carme Fons, Ana Fontalba, Enrique Galán, P. Gallano, María José Gamundi, Pedro Luis García, María del Mar del Aguila García, María García‐Barcina, María Jesús Garcia-Catalan, Àngels García‐Cazorla, Sixto García‐Miñaúr, Juan José García‐Peñas, María Teresa García‐Silva, Rosa Gassio, Esther Geán, Belén Gil, Sarenur Gökben, Luís Miguel González, Verónica Gómez González, Julieta González, Gloria González, Encarna Guillén‐Navarro, Míriam Guitart, Montserrat Guitet, Juan Manuel Gutiérrez, Eva Gutiérrez, J L Herranz, Gemma Iglesias, Iva Karačić, Carlos Lahoz, José I. Lao, Pablo Lapunzina, María Jesús Lautre-Ecenarro, María Dolores Lluch, Laura López de Frutos, Asunción López-Ariztegui, Alfons Macaya, Rosario Marín, Charles M. Lourenço Marquez, Elena Martín, Beatriz Martínez, Eduardo Martínez-Salcedo, María José Mas, Gonzálo Mateo, Pilar Méndez, Amparo Morant Jimenez, Sira Moreno, Fernando Mulas, Juan Narbona, A. Nascimento, M Nieto, Tania Fabiola Nunes, Núria Núñez, María Obón, Ignacio Onsurbe, C. Ortez, Emilio Orts, Francisco Martı́nez, Rafael Parrilla, Samuel Ignacio Pascual Pascual, Ana Patiño-Garcı́a, María Pérez-Poyato, Belén Pérez‐Dueñas, Pilar Póo, Eliodoro Puche, Feliciano J. Ramos, Miquel Raspall‐Chaure, Ana Roche, Susana Roldán, Jordi Rosell, César Ruiz, María Luz Ruiz-Falcó, Maria Russi, Jordi Samarra, Victoria San Antonio‐Arce, Iván Sánchez Sánchez, Xavier Sanmartin, Ana Sans, Alfredo Santacana, Sabine Scholl‐Bürgi, Núria Serrano, Mercedes Serrano, Pilar Martin-Tamayo, Adrián Tendero, Jaime Torrents, Diego Tortosa, Emma Triviño, L. Troncoso, Eulàlia Turón-Viñas, Pilar Vázquez, Carlos Vázquez, Ramón Velázquez, Clara Ventura, Alfonso Verdú, Anna Vernet, Miguel Tomás Vila, Cristina Villar,

Autism Spectrum Disorder Research

Abstract Rett syndrome (RTT) is a severe neurological disorder usually caused by mutations in the MECP2 gene. Since the MECP2 gene is located on the X chromosome, X chromosome inactivation (XCI) could play a role in the wide range of phenotypic variation of RTT patients; however, classical methylation-based protocols to evaluate XCI could not determine whether the preferentially inactivated X chromosome carried the mutant or the wild-type allele. Therefore, we developed an allele-specific methylation-based assay to evaluate methylation at the loci of several recurrent MECP2 mutations. We analyzed the XCI patterns in the blood of 174 RTT patients, but we did not find a clear correlation between XCI and the clinical presentation. We also compared XCI in blood and brain cortex samples of two patients and found differences between XCI patterns in these tissues. However, RTT mainly being a neurological disease complicates the establishment of a correlation between the XCI in blood and the clinical presentation of the patients. Furthermore, we analyzed MECP2 transcript levels and found differences from the expected levels according to XCI. Many factors other than XCI could affect the RTT phenotype, which in combination could influence the clinical presentation of RTT patients to a greater extent than slight variations in the XCI pattern.