Insight into disease processes of fragil X premutation carriers associated pathologies: expression-profile characterization and identification of a novel pathogenic mechanisms
- Autores: Elisabet Mateu Huertas
- Directores de la Tesis: Xavier Estivill Palleja (codir. tes.), Eulàlia Martí (codir. tes.)
- Lectura: En la Universitat Pompeu Fabra ( España ) en 2013
- Idioma: español
- Tribunal Calificador de la Tesis: Isidro Ferrer Abizanda (presid.), Esther Pérez Navarro (secret.), Yolanda Espinosa Parrilla (voc.)
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
Hombres portadores de la premutación (PM) en el gen asociado Frágil X (FMR1), que presentan entre 55-200 repeticiones de CGG, están en riesgo de desarrollar el síndrome de temblor/ataxia asociado al X frágil (FXTAS), y las mujeres fallo ovárico precoz (POF1). Estas enfermedades son causadas por la función tóxica del ARN mensajero. Alteraciones funcionales de varios reguladores de la expresión génica han sido propuesto como causa subyacente a estos trastornos . En esta tesis, se han caracterizado las alteraciones asociadas al transcriptoma de la premutación en el FMR1 y analizado la relevancia biogénesis y la actividad de un pequeño ARN, formado por CGG repetidos (sCGG), en la disfunción neuronal relacionada con la PM del FMR1. En sangre de portadores de la premutación en el FMR1 (fXPCs) se ha detectado una fuerte desregulación de genes enriquecido en vías biológicas relevantes en FXTAS. También hemos identificado un gen desregulado (EAP1) que puede ser la base POF1 en mujeres fXPCs. Además, hemos encontrado un aumento en los niveles de sCGG en diferentes modelos de FMR1-PM y demostramos su actividad neurotóxica a través de un mecanismo dependiente en la maquinaria de silenciamiento génico. Proponemos que la actividad de sCGG puede contribuir a causar perturbaciones en el transcriptoma y desencadenar consecuencias patógenas . En general , ofrecemos un nuevo enfoque en proceso de la enfermedad y un diagnóstico más exacto para la gran variedad de fenotipos asociados con fXPCs .
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