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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| creator | Giannandrea, Maila Guarnieri, Fabrizia C Gehring, Niels H Monzani, Elena Benfenati, Fabio Kulozik, Andreas E Valtorta, Flavia |
| 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. |
| doi_str_mv | 10.1371/journal.pone.0067724 |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0067724</identifier><identifier>PMID: 23818987</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Autism ; Biology ; Blotting, Northern ; Cell culture ; Cells, Cultured ; Clustering ; Codon, Nonsense ; Decay ; Epilepsy ; Epilepsy - genetics ; Epilepsy - metabolism ; Female ; Gene Expression ; Genes ; Genetic Diseases, X-Linked - genetics ; Genetic Diseases, X-Linked - metabolism ; Genotype & phenotype ; HeLa Cells ; Hippocampus ; Hippocampus - cytology ; Hippocampus - metabolism ; Human pathology ; Humans ; Kinases ; Male ; Males ; Medicine ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microscopy, Fluorescence ; Microtubule-Associated Proteins - metabolism ; Mimicry ; mRNA turnover ; Mutation ; Neurons ; Neurons - metabolism ; Neurosciences ; Nonsense Mediated mRNA Decay ; Nonsense mutation ; Phosphoproteins ; Phosphorylation ; Proteins ; Rats ; Rats, Sprague-Dawley ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; Rodents ; Synapsin I ; Synapsins - genetics ; Synapsins - metabolism ; Synaptic vesicles ; Synaptogenesis ; Transcription</subject><ispartof>PloS one, 2013-06, Vol.8 (6), p.e67724-e67724</ispartof><rights>2013 Giannandrea et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Giannandrea et al 2013 Giannandrea et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4414-2233b8fa483725eff069f60a1e2fdfbbdd8d8cb23e4badaa7ecea542f000131c3</citedby><cites>FETCH-LOGICAL-c4414-2233b8fa483725eff069f60a1e2fdfbbdd8d8cb23e4badaa7ecea542f000131c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3688603/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3688603/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2100,2926,23864,27922,27923,53789,53791,79370,79371</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23818987$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Gonzalez-Alegre, Pedro</contributor><creatorcontrib>Giannandrea, Maila</creatorcontrib><creatorcontrib>Guarnieri, Fabrizia C</creatorcontrib><creatorcontrib>Gehring, Niels H</creatorcontrib><creatorcontrib>Monzani, Elena</creatorcontrib><creatorcontrib>Benfenati, Fabio</creatorcontrib><creatorcontrib>Kulozik, Andreas E</creatorcontrib><creatorcontrib>Valtorta, Flavia</creatorcontrib><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><title>PloS one</title><addtitle>PLoS One</addtitle><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.</description><subject>Animals</subject><subject>Autism</subject><subject>Biology</subject><subject>Blotting, Northern</subject><subject>Cell culture</subject><subject>Cells, Cultured</subject><subject>Clustering</subject><subject>Codon, Nonsense</subject><subject>Decay</subject><subject>Epilepsy</subject><subject>Epilepsy - genetics</subject><subject>Epilepsy - metabolism</subject><subject>Female</subject><subject>Gene Expression</subject><subject>Genes</subject><subject>Genetic Diseases, X-Linked - genetics</subject><subject>Genetic Diseases, X-Linked - metabolism</subject><subject>Genotype & phenotype</subject><subject>HeLa Cells</subject><subject>Hippocampus</subject><subject>Hippocampus - 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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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23818987</pmid><doi>10.1371/journal.pone.0067724</doi><oa>free_for_read</oa></addata></record> |
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| ispartof | PloS one, 2013-06, Vol.8 (6), p.e67724-e67724 |
| issn | 1932-6203 1932-6203 |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Animals Autism Biology Blotting, Northern Cell culture Cells, Cultured Clustering Codon, Nonsense Decay Epilepsy Epilepsy - genetics Epilepsy - metabolism Female Gene Expression Genes Genetic Diseases, X-Linked - genetics Genetic Diseases, X-Linked - metabolism Genotype & phenotype HeLa Cells Hippocampus Hippocampus - cytology Hippocampus - metabolism Human pathology Humans Kinases Male Males Medicine Mice Mice, Inbred C57BL Mice, Knockout Microscopy, Fluorescence Microtubule-Associated Proteins - metabolism Mimicry mRNA turnover Mutation Neurons Neurons - metabolism Neurosciences Nonsense Mediated mRNA Decay Nonsense mutation Phosphoproteins Phosphorylation Proteins Rats Rats, Sprague-Dawley RNA, Messenger - genetics RNA, Messenger - metabolism Rodents Synapsin I Synapsins - genetics Synapsins - metabolism Synaptic vesicles Synaptogenesis Transcription |
| 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 |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-14T00%3A36%3A28IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Nonsense-mediated%20mRNA%20decay%20and%20loss-of-function%20of%20the%20protein%20underlie%20the%20X-linked%20epilepsy%20associated%20with%20the%20W356%C3%97%20mutation%20in%20synapsin%20I&rft.jtitle=PloS%20one&rft.au=Giannandrea,%20Maila&rft.date=2013-06-20&rft.volume=8&rft.issue=6&rft.spage=e67724&rft.epage=e67724&rft.pages=e67724-e67724&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0067724&rft_dat=%3Cproquest_plos_%3E3001338281%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1370183807&rft_id=info:pmid/23818987&rft_doaj_id=oai_doaj_org_article_762f4b1c76494f899a150edf23f724ff&rfr_iscdi=true |