Nonsense-mediated mRNA decay and loss-of-function of the protein underlie the X-linked epilepsy associated with the W356× mutation in synapsin I.

Synapsins are a family of neuronal phosphoproteins associated with the cytosolic surface of synaptic vesicles. Experimental evidence suggests a role for synapsins in synaptic vesicle clustering and recycling at the presynaptic terminal, as well as in neuronal development and synaptogenesis. Synapsin...

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Autores principales:	Maila Giannandrea, Fabrizia C Guarnieri, Niels H Gehring, Elena Monzani, Fabio Benfenati, Andreas E Kulozik, Flavia Valtorta
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/762f4b1c76494f899a150edf23f724ff
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spelling	oai:doaj.org-article:762f4b1c76494f899a150edf23f724ff2021-11-18T07:40:54ZNonsense-mediated mRNA decay and loss-of-function of the protein underlie the X-linked epilepsy associated with the W356× mutation in synapsin I.1932-620310.1371/journal.pone.0067724https://doaj.org/article/762f4b1c76494f899a150edf23f724ff2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23818987/?tool=EBIhttps://doaj.org/toc/1932-6203Synapsins are a family of neuronal phosphoproteins associated with the cytosolic surface of synaptic vesicles. Experimental evidence suggests a role for synapsins in synaptic vesicle clustering and recycling at the presynaptic terminal, as well as in neuronal development and synaptogenesis. Synapsin knock-out (Syn1(-/-) ) mice display an epileptic phenotype and mutations in the SYN1 gene have been identified in individuals affected by epilepsy and/or autism spectrum disorder. We investigated the impact of the c.1067G>A nonsense transition, the first mutation described in a family affected by X-linked syndromic epilepsy, on the expression and functional properties of the synapsin I protein. We found that the presence of a premature termination codon in the human SYN1 transcript renders it susceptible to nonsense-mediated mRNA decay (NMD). Given that the NMD efficiency is highly variable among individuals and cell types, we investigated also the effects of expression of the mutant protein and found that it is expressed at lower levels compared to wild-type synapsin I, forms perinuclear aggregates and is unable to reach presynaptic terminals in mature hippocampal neurons grown in culture. Taken together, these data indicate that in patients carrying the W356× mutation the function of synapsin I is markedly impaired, due to both the strongly decreased translation and the altered function of the NMD-escaped protein, and support the value of Syn1(-/-) mice as an experimental model mimicking the human pathology.Maila GiannandreaFabrizia C GuarnieriNiels H GehringElena MonzaniFabio BenfenatiAndreas E KulozikFlavia ValtortaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 6, p e67724 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Maila Giannandrea Fabrizia C Guarnieri Niels H Gehring Elena Monzani Fabio Benfenati Andreas E Kulozik Flavia Valtorta Nonsense-mediated mRNA decay and loss-of-function of the protein underlie the X-linked epilepsy associated with the W356× mutation in synapsin I.
description	Synapsins are a family of neuronal phosphoproteins associated with the cytosolic surface of synaptic vesicles. Experimental evidence suggests a role for synapsins in synaptic vesicle clustering and recycling at the presynaptic terminal, as well as in neuronal development and synaptogenesis. Synapsin knock-out (Syn1(-/-) ) mice display an epileptic phenotype and mutations in the SYN1 gene have been identified in individuals affected by epilepsy and/or autism spectrum disorder. We investigated the impact of the c.1067G>A nonsense transition, the first mutation described in a family affected by X-linked syndromic epilepsy, on the expression and functional properties of the synapsin I protein. We found that the presence of a premature termination codon in the human SYN1 transcript renders it susceptible to nonsense-mediated mRNA decay (NMD). Given that the NMD efficiency is highly variable among individuals and cell types, we investigated also the effects of expression of the mutant protein and found that it is expressed at lower levels compared to wild-type synapsin I, forms perinuclear aggregates and is unable to reach presynaptic terminals in mature hippocampal neurons grown in culture. Taken together, these data indicate that in patients carrying the W356× mutation the function of synapsin I is markedly impaired, due to both the strongly decreased translation and the altered function of the NMD-escaped protein, and support the value of Syn1(-/-) mice as an experimental model mimicking the human pathology.
format	article
author	Maila Giannandrea Fabrizia C Guarnieri Niels H Gehring Elena Monzani Fabio Benfenati Andreas E Kulozik Flavia Valtorta
author_facet	Maila Giannandrea Fabrizia C Guarnieri Niels H Gehring Elena Monzani Fabio Benfenati Andreas E Kulozik Flavia Valtorta
author_sort	Maila Giannandrea
title	Nonsense-mediated mRNA decay and loss-of-function of the protein underlie the X-linked epilepsy associated with the W356× mutation in synapsin I.
title_short	Nonsense-mediated mRNA decay and loss-of-function of the protein underlie the X-linked epilepsy associated with the W356× mutation in synapsin I.
title_full	Nonsense-mediated mRNA decay and loss-of-function of the protein underlie the X-linked epilepsy associated with the W356× mutation in synapsin I.
title_fullStr	Nonsense-mediated mRNA decay and loss-of-function of the protein underlie the X-linked epilepsy associated with the W356× mutation in synapsin I.
title_full_unstemmed	Nonsense-mediated mRNA decay and loss-of-function of the protein underlie the X-linked epilepsy associated with the W356× mutation in synapsin I.
title_sort	nonsense-mediated mrna decay and loss-of-function of the protein underlie the x-linked epilepsy associated with the w356× mutation in synapsin i.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/762f4b1c76494f899a150edf23f724ff
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Nonsense-mediated mRNA decay and loss-of-function of the protein underlie the X-linked epilepsy associated with the W356× mutation in synapsin I.

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