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An empirical pipeline for personalized diagnosis of Lafora disease mutations

Lafora disease (LD) is a fatal childhood dementia characterized by progressive myoclonic epilepsy manifesting in the teenage years, rapid neurological decline, and death typically within ten years of onset. Mutations in either EPM2A, encoding the glycogen phosphatase laforin, or EPM2B, encoding the...

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Detalles Bibliográficos
Autores principales: Brewer, M. Kathryn, Machio-Castello, Maria, Viana, Rosa, Wayne, Jeremiah L., Kuchtová, Andrea, Simmons, Zoe R., Sternbach, Sarah, Li, Sheng, García-Gimeno, Maria Adelaida, Serratosa, Jose M., Sanz, Pascual, Vander Kooi, Craig W., Gentry, Matthew S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564118/
https://www.ncbi.nlm.nih.gov/pubmed/34755096
http://dx.doi.org/10.1016/j.isci.2021.103276
Descripción
Sumario:Lafora disease (LD) is a fatal childhood dementia characterized by progressive myoclonic epilepsy manifesting in the teenage years, rapid neurological decline, and death typically within ten years of onset. Mutations in either EPM2A, encoding the glycogen phosphatase laforin, or EPM2B, encoding the E3 ligase malin, cause LD. Whole exome sequencing has revealed many EPM2A variants associated with late-onset or slower disease progression. We established an empirical pipeline for characterizing the functional consequences of laforin missense mutations in vitro using complementary biochemical approaches. Analysis of 26 mutations revealed distinct functional classes associated with different outcomes that were supported by clinical cases. For example, F321C and G279C mutations have attenuated functional defects and are associated with slow progression. This pipeline enabled rapid characterization and classification of newly identified EPM2A mutations, providing clinicians and researchers genetic information to guide treatment of LD patients.