Identification of the sphingolipid desaturase degs1 as a novel gene for a leukodystrophy with therapeutic hope
- Autores: Devesh Chandra Pant
- Directores de la Tesis: Aurora Pujol Onofre (dir. tes.), Estephane Fourcade (codir. tes.), Cristina Pujades Corbi (tut. tes.)
- Lectura: En la Universitat Pompeu Fabra ( España ) en 2018
- Idioma: español
- Tribunal Calificador de la Tesis: Adolfo López de Munain Arregui (presid.), Maria Victoria Campuzano Uceda (secret.), Manuel Portero Otin (voc.)
- Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad Pompeu Fabra
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
In spite of recent advances in understanding the genetic bases of leukodystrophies, a large number of clinical cases remain unexplained, suggesting that many leukodystrophy-associated genes have yet to be identified. Here we report 18 patients from 12 families with biallelic deleterious variants in the DEGS1 gene identified via WES. DEGS1 encodes an enzyme which catalyzes the conversion of dihydroceramide to ceramide. Common features among the patients include severe cerebellum atrophy, thinning of the corpus callosum and hypomyelination suggesting a critical role of DEGS1 in the central nervous system.
Using patient’s fibroblasts, we evidenced abnormal biochemical profiles. Knockdown of degs1 in zebrafish recapitulated the biochemical imbalance, showed impaired locomotor abilities and weak myelination. Moreover, a widely used drug for neurological disorders, fingolimod, able to normalized the toxic effects associated due to impaired DEGS1. These results pave the way to clinical translation, illustrating the transformative impact of genomics in patient care.
