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Recurrent SLC1A2 variants cause epilepsy via a dominant negative mechanism
SLC1A2 is a trimeric transporter essential for clearing glutamate from neuronal synapses. Recurrent de novo SLC1A2 missense variants cause a severe, early onset developmental and epileptic encephalopathy via an unclear mechanism. We demonstrate that all 3 variants implicated in this condition locali...
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| Published in: | Annals of neurology 2019-06, Vol.85 (6), p.921-926 |
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| Main Authors: | , , , , , , , , , , , , , , , |
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| cites | cdi_FETCH-LOGICAL-c4437-27aaccbf03ae36ec85c87d43288696f101330f3e38e7e9ec220d96c3c78feca33 |
| container_end_page | 926 |
| container_issue | 6 |
| container_start_page | 921 |
| container_title | Annals of neurology |
| container_volume | 85 |
| creator | Stergachis, Andrew B. Pujol‐Giménez, Jonai Gyimesi, Gergely Fuster, Daniel Albano, Giusppe Troxler, Marina Picker, Jonathan Rosenberg, Paul A. Bergin, Ann Peters, Jurriaan El Achkar, Christelle Moufawad Harini, Chellamani Manzi, Shannon Rotenberg, Alexander Hediger, Matthias A. Rodan, Lance H. |
| description | SLC1A2 is a trimeric transporter essential for clearing glutamate from neuronal synapses. Recurrent de novo SLC1A2 missense variants cause a severe, early onset developmental and epileptic encephalopathy via an unclear mechanism. We demonstrate that all 3 variants implicated in this condition localize to the trimerization domain of SLC1A2, and that the Leu85Pro variant acts via a dominant negative mechanism to reduce, but not eliminate, wild‐type SLC1A2 protein localization and function. Finally, we demonstrate that treatment of a 20‐month‐old SLC1A2‐related epilepsy patient with the SLC1A2‐modulating agent ceftriaxone did not result in a significant change in daily spasm count. ANN NEUROL 2019;85:921–926. |
| doi_str_mv | 10.1002/ana.25477 |
| format | article |
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Recurrent de novo SLC1A2 missense variants cause a severe, early onset developmental and epileptic encephalopathy via an unclear mechanism. We demonstrate that all 3 variants implicated in this condition localize to the trimerization domain of SLC1A2, and that the Leu85Pro variant acts via a dominant negative mechanism to reduce, but not eliminate, wild‐type SLC1A2 protein localization and function. Finally, we demonstrate that treatment of a 20‐month‐old SLC1A2‐related epilepsy patient with the SLC1A2‐modulating agent ceftriaxone did not result in a significant change in daily spasm count. ANN NEUROL 2019;85:921–926.</description><identifier>ISSN: 0364-5134</identifier><identifier>EISSN: 1531-8249</identifier><identifier>DOI: 10.1002/ana.25477</identifier><identifier>PMID: 30937933</identifier><language>eng</language><publisher>Hoboken, USA: John Wiley & Sons, Inc</publisher><subject>Amino Acid Sequence ; Ceftriaxone ; Ceftriaxone - therapeutic use ; Child, Preschool ; Encephalopathy ; Epilepsy ; Epilepsy, Generalized - diagnosis ; Epilepsy, Generalized - drug therapy ; Epilepsy, Generalized - genetics ; Excitatory Amino Acid Transporter 2 - chemistry ; Excitatory Amino Acid Transporter 2 - genetics ; Female ; Genetic Variation - genetics ; HEK293 Cells ; Humans ; Infant ; Infant, Newborn ; Localization ; Male ; Protein Structure, Secondary ; Synapses</subject><ispartof>Annals of neurology, 2019-06, Vol.85 (6), p.921-926</ispartof><rights>2019 American Neurological Association</rights><rights>2019 American Neurological Association.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4437-27aaccbf03ae36ec85c87d43288696f101330f3e38e7e9ec220d96c3c78feca33</citedby><cites>FETCH-LOGICAL-c4437-27aaccbf03ae36ec85c87d43288696f101330f3e38e7e9ec220d96c3c78feca33</cites><orcidid>0000-0002-6725-2814</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30937933$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Stergachis, Andrew B.</creatorcontrib><creatorcontrib>Pujol‐Giménez, Jonai</creatorcontrib><creatorcontrib>Gyimesi, Gergely</creatorcontrib><creatorcontrib>Fuster, Daniel</creatorcontrib><creatorcontrib>Albano, Giusppe</creatorcontrib><creatorcontrib>Troxler, Marina</creatorcontrib><creatorcontrib>Picker, Jonathan</creatorcontrib><creatorcontrib>Rosenberg, Paul A.</creatorcontrib><creatorcontrib>Bergin, Ann</creatorcontrib><creatorcontrib>Peters, Jurriaan</creatorcontrib><creatorcontrib>El Achkar, Christelle Moufawad</creatorcontrib><creatorcontrib>Harini, Chellamani</creatorcontrib><creatorcontrib>Manzi, Shannon</creatorcontrib><creatorcontrib>Rotenberg, Alexander</creatorcontrib><creatorcontrib>Hediger, Matthias A.</creatorcontrib><creatorcontrib>Rodan, Lance H.</creatorcontrib><title>Recurrent SLC1A2 variants cause epilepsy via a dominant negative mechanism</title><title>Annals of neurology</title><addtitle>Ann Neurol</addtitle><description>SLC1A2 is a trimeric transporter essential for clearing glutamate from neuronal synapses. Recurrent de novo SLC1A2 missense variants cause a severe, early onset developmental and epileptic encephalopathy via an unclear mechanism. We demonstrate that all 3 variants implicated in this condition localize to the trimerization domain of SLC1A2, and that the Leu85Pro variant acts via a dominant negative mechanism to reduce, but not eliminate, wild‐type SLC1A2 protein localization and function. Finally, we demonstrate that treatment of a 20‐month‐old SLC1A2‐related epilepsy patient with the SLC1A2‐modulating agent ceftriaxone did not result in a significant change in daily spasm count. ANN NEUROL 2019;85:921–926.</description><subject>Amino Acid Sequence</subject><subject>Ceftriaxone</subject><subject>Ceftriaxone - therapeutic use</subject><subject>Child, Preschool</subject><subject>Encephalopathy</subject><subject>Epilepsy</subject><subject>Epilepsy, Generalized - diagnosis</subject><subject>Epilepsy, Generalized - drug therapy</subject><subject>Epilepsy, Generalized - genetics</subject><subject>Excitatory Amino Acid Transporter 2 - chemistry</subject><subject>Excitatory Amino Acid Transporter 2 - genetics</subject><subject>Female</subject><subject>Genetic Variation - genetics</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Infant</subject><subject>Infant, Newborn</subject><subject>Localization</subject><subject>Male</subject><subject>Protein Structure, Secondary</subject><subject>Synapses</subject><issn>0364-5134</issn><issn>1531-8249</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNp1kU1vEzEQhi0EIqFw4A8gS1zKYVPb4_3wBSmKoAVFIPFxtibObOto1xvsbKr8e0wTIkDi5MM8eub1vIy9lGImhVBXGHCmSl3Xj9hUliCLRmnzmE0FVLooJegJe5bSRghhKimesgkIA7UBmLKPX8iNMVLY8a_LhZwrvsfoMewSdzgm4rT1HW3Tge89cuTrofchj3mgW9z5PfGe3B0Gn_rn7EmLXaIXp_eCfX__7tviplh-vv6wmC8LpzXUhaoRnVu1ApCgIteUrqnXGlTTVKZqpZAAogWChmoy5JQSa1M5cHXTkkOAC_b26N2Oq57WLmeP2Nlt9D3Ggx3Q278nwd_Z22FvqyYfS4osuDwJ4vBjpLSzvU-Oug4DDWOyeaOSpjSgM_r6H3QzjDHk72VKaahyZJmpN0fKxSGlSO05jBT2V0M2N2QfGsrsqz_Tn8nflWTg6gjc58Mf_m-y80_zo_InXYuaVQ</recordid><startdate>201906</startdate><enddate>201906</enddate><creator>Stergachis, Andrew B.</creator><creator>Pujol‐Giménez, Jonai</creator><creator>Gyimesi, Gergely</creator><creator>Fuster, Daniel</creator><creator>Albano, Giusppe</creator><creator>Troxler, Marina</creator><creator>Picker, Jonathan</creator><creator>Rosenberg, Paul A.</creator><creator>Bergin, Ann</creator><creator>Peters, Jurriaan</creator><creator>El Achkar, Christelle Moufawad</creator><creator>Harini, Chellamani</creator><creator>Manzi, Shannon</creator><creator>Rotenberg, Alexander</creator><creator>Hediger, Matthias A.</creator><creator>Rodan, Lance H.</creator><general>John Wiley & Sons, Inc</general><general>Wiley Subscription Services, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7U7</scope><scope>C1K</scope><scope>K9.</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-6725-2814</orcidid></search><sort><creationdate>201906</creationdate><title>Recurrent SLC1A2 variants cause epilepsy via a dominant negative mechanism</title><author>Stergachis, Andrew B. ; 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Recurrent de novo SLC1A2 missense variants cause a severe, early onset developmental and epileptic encephalopathy via an unclear mechanism. We demonstrate that all 3 variants implicated in this condition localize to the trimerization domain of SLC1A2, and that the Leu85Pro variant acts via a dominant negative mechanism to reduce, but not eliminate, wild‐type SLC1A2 protein localization and function. Finally, we demonstrate that treatment of a 20‐month‐old SLC1A2‐related epilepsy patient with the SLC1A2‐modulating agent ceftriaxone did not result in a significant change in daily spasm count. ANN NEUROL 2019;85:921–926.</abstract><cop>Hoboken, USA</cop><pub>John Wiley & Sons, Inc</pub><pmid>30937933</pmid><doi>10.1002/ana.25477</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0002-6725-2814</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Annals of neurology, 2019-06, Vol.85 (6), p.921-926 |
| issn | 0364-5134 1531-8249 |
| language | eng |
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| subjects | Amino Acid Sequence Ceftriaxone Ceftriaxone - therapeutic use Child, Preschool Encephalopathy Epilepsy Epilepsy, Generalized - diagnosis Epilepsy, Generalized - drug therapy Epilepsy, Generalized - genetics Excitatory Amino Acid Transporter 2 - chemistry Excitatory Amino Acid Transporter 2 - genetics Female Genetic Variation - genetics HEK293 Cells Humans Infant Infant, Newborn Localization Male Protein Structure, Secondary Synapses |
| title | Recurrent SLC1A2 variants cause epilepsy via a dominant negative mechanism |
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