An empirical pipeline for personalized diagnosis of Lafora disease mutations

Summary: 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, enco...

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Autores principales:	M. Kathryn Brewer, Maria Machio-Castello, Rosa Viana, Jeremiah L. Wayne, Andrea Kuchtová, Zoe R. Simmons, Sarah Sternbach, Sheng Li, Maria Adelaida García-Gimeno, Jose M. Serratosa, Pascual Sanz, Craig W. Vander Kooi, Matthew S. Gentry
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Disease Biochemistry Structural biology Biophysics Science Q
Acceso en línea:	https://doaj.org/article/08a505503d644df58c43dc58bd8a2937
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spelling	oai:doaj.org-article:08a505503d644df58c43dc58bd8a29372021-11-20T05:09:12ZAn empirical pipeline for personalized diagnosis of Lafora disease mutations2589-004210.1016/j.isci.2021.103276https://doaj.org/article/08a505503d644df58c43dc58bd8a29372021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2589004221012451https://doaj.org/toc/2589-0042Summary: 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.M. Kathryn BrewerMaria Machio-CastelloRosa VianaJeremiah L. WayneAndrea KuchtováZoe R. SimmonsSarah SternbachSheng LiMaria Adelaida García-GimenoJose M. SerratosaPascual SanzCraig W. Vander KooiMatthew S. GentryElsevierarticleDiseaseBiochemistryStructural biologyBiophysicsScienceQENiScience, Vol 24, Iss 11, Pp 103276- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Disease Biochemistry Structural biology Biophysics Science Q
spellingShingle	Disease Biochemistry Structural biology Biophysics Science Q M. Kathryn Brewer Maria Machio-Castello Rosa Viana Jeremiah L. Wayne Andrea Kuchtová Zoe R. Simmons Sarah Sternbach Sheng Li Maria Adelaida García-Gimeno Jose M. Serratosa Pascual Sanz Craig W. Vander Kooi Matthew S. Gentry An empirical pipeline for personalized diagnosis of Lafora disease mutations
description	Summary: 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.
format	article
author	M. Kathryn Brewer Maria Machio-Castello Rosa Viana Jeremiah L. Wayne Andrea Kuchtová Zoe R. Simmons Sarah Sternbach Sheng Li Maria Adelaida García-Gimeno Jose M. Serratosa Pascual Sanz Craig W. Vander Kooi Matthew S. Gentry
author_facet	M. Kathryn Brewer Maria Machio-Castello Rosa Viana Jeremiah L. Wayne Andrea Kuchtová Zoe R. Simmons Sarah Sternbach Sheng Li Maria Adelaida García-Gimeno Jose M. Serratosa Pascual Sanz Craig W. Vander Kooi Matthew S. Gentry
author_sort	M. Kathryn Brewer
title	An empirical pipeline for personalized diagnosis of Lafora disease mutations
title_short	An empirical pipeline for personalized diagnosis of Lafora disease mutations
title_full	An empirical pipeline for personalized diagnosis of Lafora disease mutations
title_fullStr	An empirical pipeline for personalized diagnosis of Lafora disease mutations
title_full_unstemmed	An empirical pipeline for personalized diagnosis of Lafora disease mutations
title_sort	empirical pipeline for personalized diagnosis of lafora disease mutations
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/08a505503d644df58c43dc58bd8a2937
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An empirical pipeline for personalized diagnosis of Lafora disease mutations

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