{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T11:45:37Z","timestamp":1791978337007,"version":"4.4.0"},"reference-count":51,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T00:00:00Z","timestamp":1662595200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      Rare inherited missense variants in\n                      <jats:italic>SLC32A1<\/jats:italic>\n                      , the gene that encodes the vesicular gamma\u2010aminobutyric acid (GABA) transporter, have recently been shown to cause genetic epilepsy with febrile seizures plus. We aimed to clarify if de novo missense variants in\n                      <jats:italic>SLC32A1<\/jats:italic>\n                      can also cause epilepsy with impaired neurodevelopment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Using exome sequencing, we identified four individuals with a developmental and epileptic encephalopathy and de novo missense variants in\n                      <jats:italic>SLC32A1<\/jats:italic>\n                      . To assess causality, we performed functional evaluation of the identified variants in a murine neuronal cell culture model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The main phenotype comprises moderate\u2010to\u2010severe intellectual disability, infantile\u2010onset epilepsy within the first 18\u00a0months of life, and a choreiform, dystonic, or dyskinetic movement disorder. In silico modeling and functional analyses reveal that three of these variants, which are located in helices that line the putative GABA transport pathway, result in reduced quantal size, consistent with impaired filling of synaptic vesicles with GABA. The fourth variant, located in the vesicular gamma\u2010aminobutyric acid N\u2010terminus, does not affect quantal size, but increases presynaptic release probability, leading to more severe synaptic depression during high\u2010frequency stimulation. Thus, variants in vesicular gamma\u2010aminobutyric acid can impair GABAergic neurotransmission through at least two mechanisms, by affecting synaptic vesicle filling and by altering synaptic short\u2010term plasticity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      This work establishes de novo missense variants in\n                      <jats:italic>SLC32A1<\/jats:italic>\n                      as a novel cause of a developmental and epileptic encephalopathy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Summary for Social Media If Published<\/jats:title>\n                    <jats:p>\n                      <jats:list>\n                        <jats:list-item>\n                          <jats:p>@platzer_k @lemke_johannes @RamiJamra @Nirgalito @GeneDx<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The SLC family 32 Member 1 (SLC32A1) is the only protein identified to date, that loads gamma\u2010aminobutyric acid (GABA) and glycine into synaptic vesicles, and is therefore also known as the vesicular GABA transporter (VGAT) or vesicular inhibitory amino acid transporter (VIAAT). Rare inherited missense variants in SLC32A1, the gene that encodes VGAT\/vesicular inhibitory amino acid transporter, have recently been shown to cause genetic epilepsy with febrile seizures plus.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            We aimed to clarify if de novo missense variants in\n                            <jats:italic>SLC32A1<\/jats:italic>\n                            can also cause epilepsy with impaired neurodevelopment.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            We report on four individuals with de novo missense variants in\n                            <jats:italic>SLC32A1<\/jats:italic>\n                            and a developmental and epileptic encephalopathy with infantile onset epilepsy. We establish causality of the variants via in silico modeling and their functional evaluation in a murine neuronal cell culture model.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            <jats:italic>SLC32A1<\/jats:italic>\n                            variants represent a novel genetic etiology in neurodevelopmental disorders with epilepsy and a new GABA\u2010related disease mechanism.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                      ANN NEUROL 2022;92:958\u2013973\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.26485","type":"journal-article","created":{"date-parts":[[2022,8,19]],"date-time":"2022-08-19T06:38:13Z","timestamp":1660891093000},"page":"958-973","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["De Novo Missense Variants in\n                    <scp>\n                      <i>SLC32A1<\/i>\n                    <\/scp>\n                    Cause a Developmental and Epileptic Encephalopathy Due to Impaired\n                    <scp>GABAergic<\/scp>\n                    Neurotransmission"],"prefix":"10.1002","volume":"92","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6127-6308","authenticated-orcid":false,"given":"Konrad","family":"Platzer","sequence":"first","affiliation":[{"name":"Institute of Human Genetics University of Leipzig Medical Center  Leipzig 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