Identification of the sphingolipid desaturase DEGS1 as a novel gene for a leukodystrophy in therapeutic hope

Pant, Devesh Chandra

Identification of the sphingolipid desaturase DEGS1 as a novel gene for a leukodystrophy in therapeutic hope

Document Type

Doctoral thesis
Published Version

Author

Pant, Devesh Chandra

Director

Pujol, Aurora
Fourcade, Stéphane

Publication Date

2018-10-05

Pages

184 p.

License

Citation

Pant, D. Identification of the sphingolipid desaturase DEGS1 as a novel gene for a leukodystrophy in therapeutic hope. Universitat Pompeu Fabra; 2018. handle: http://hdl.handle.net/10803/664936

This citation was generated automatically.

Doctoral program

Programa de doctorat en Biomedicina

Abstract

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.
El hecho de que un gran número de casos clínicos de leucodistrofias sigan sin explicar sugiere que muchos de los genes asociados a esta enfermedad estarían aún por identificar. Secuenciando el exoma completo de 18 pacientes de 12 familias hemos encontrado variantes deletéreas bialélicas en el gen DEGS1, un gen que codifica para una enzima que cataliza la conversión de dihidroceramida a ceramida. Las características comunes entre estos pacientes incluyen atrofia grave del cerebelo, delgadez del cuerpo calloso e hipomielinización, sugiriendo un papel crítico de la proteína DEGS1 en el SNC. Sus fibroblastos envidencian un perfil bioquímico anormal. Hemos comprobado que un modelo de knockdown del gen degs1 en pez cebra muestra capacidades locomotoras alteradas, desequilibrio bioquímico y una mielinización débil. Hemos conseguido normalizar sus efectos tóxicos con fingolimod, un fármaco ampliamente usado para trastornos neurológicos. Son resultados que ilustran el impacto transformador de la genómica en la atención al paciente, abriendo un nuevo camino en la clínica traslacional.

Keywords

Ultra-rare disease, Dihydroceramide desaturase, Oligodendrocytes, Fingolimod, Zebrafish, Secuenciación completa de exoma, Leucodistrofia, Esfingolípidos, Especies reactivas de oxígeno, Terapéutica