{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T02:14:39Z","timestamp":1780107279788,"version":"3.54.0"},"reference-count":81,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2020,4,29]],"date-time":"2020-04-29T00:00:00Z","timestamp":1588118400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","award":["RG65966"],"award-info":[{"award-number":["RG65966"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp; Gen Med"],"published-print":{"date-parts":[[2020,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Cys\u2010loop receptors control neuronal excitability in the brain and their dysfunction results in numerous neurological disorders. Recently, six missense variants in\n                      <jats:italic>GABRA2<\/jats:italic>\n                      , a member of this family, have been associated with early infantile epileptic encephalopathy (EIEE). We identified a novel de novo missense variant in\n                      <jats:italic>GABRA2<\/jats:italic>\n                      in a patient with EIEE and performed protein structural analysis of the seven variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The novel variant was identified by trio whole\u2010genome sequencing\n                      <jats:italic>.<\/jats:italic>\n                      We performed protein structural analysis of the seven variants, and compared them to previously reported pathogenic mutations at equivalent positions in other Cys\u2010loop receptors. Additionally, we studied the distribution of disease\u2010associated variants in the transmembrane helices of these proteins.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The seven variants are in the transmembrane domain, either close to the desensitization gate, the activation gate, or in inter\u2010subunit interfaces. Six of them have pathogenic mutations at equivalent positions in other Cys\u2010loop receptors, emphasizing the importance of these residues. Also, pathogenic mutations are more common in the pore\u2010lining helix, consistent with this region being highly constrained for variation in control populations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our study reports a novel pathogenic variant in\n                      <jats:italic>GABRA2<\/jats:italic>\n                      , characterizes the regions where pathogenic mutations are in the transmembrane helices, and underscores the value of considering sequence, evolutionary, and structural information as a strategy for variant interpretation of novel missense mutations.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mgg3.1106","type":"journal-article","created":{"date-parts":[[2020,4,29]],"date-time":"2020-04-29T05:42:54Z","timestamp":1588138974000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Structural analysis of pathogenic missense mutations in\n                    <i>GABRA2<\/i>\n                    and identification of a novel de novo variant in the desensitization gate"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2788-5497","authenticated-orcid":false,"given":"Alba","family":"Sanchis\u2010Juan","sequence":"first","affiliation":[{"name":"Department of Haematology University of Cambridge NHS Blood and Transplant Centre Cambridge UK"},{"name":"NIHR BioResource Cambridge University Hospitals NHS Foundation Trust Cambridge Biomedical Campus Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcia A.","family":"Hasenahuer","sequence":"additional","affiliation":[{"name":"European Molecular Biology Laboratory European Bioinformatics Institute Wellcome Genome Campus Hinxton, Cambridge UK"},{"name":"Department of Medical Genetics Cambridge Institute for Medical Research University of Cambridge Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A.","family":"Baker","sequence":"additional","affiliation":[{"name":"European Molecular Biology Laboratory European Bioinformatics Institute Wellcome Genome Campus Hinxton, Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"McTague","sequence":"additional","affiliation":[{"name":"Developmental Neurosciences Great Ormond Street Institute of Child Health University College London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katy","family":"Barwick","sequence":"additional","affiliation":[{"name":"Developmental Neurosciences Great Ormond Street Institute of Child Health University College London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manju A.","family":"Kurian","sequence":"additional","affiliation":[{"name":"Developmental Neurosciences Great Ormond Street Institute of Child Health University College London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia T.","family":"Duarte","sequence":"additional","affiliation":[{"name":"Hospital Dona Estef\u00e2nia Centro Hospitalar de Lisboa Central Lisbon Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"NIHR BioResource","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keren J.","family":"Carss","sequence":"additional","affiliation":[{"name":"Department of Haematology University of Cambridge NHS Blood and Transplant Centre Cambridge UK"},{"name":"NIHR BioResource Cambridge University Hospitals NHS Foundation Trust Cambridge Biomedical Campus Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet","family":"Thornton","sequence":"additional","affiliation":[{"name":"European Molecular Biology Laboratory European Bioinformatics Institute Wellcome Genome Campus Hinxton, Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F. 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