{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T16:47:50Z","timestamp":1791910070354,"version":"4.3.4"},"reference-count":0,"publisher":"American Society for Clinical Investigation","license":[{"start":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:00:00Z","timestamp":1791849600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key R&D Program of China","award":["2021YFA1100400"],"award-info":[{"award-number":["2021YFA1100400"]}]},{"name":"National Key R&D Program of China","award":["2020YFA0112500"],"award-info":[{"award-number":["2020YFA0112500"]}]},{"name":"National Natural Science Foundation of China","award":["32271019"],"award-info":[{"award-number":["32271019"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Natural Science Foundation of China","award":["12411530079"],"award-info":[{"award-number":["12411530079"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Natural Science Foundation of China","award":["82371464"],"award-info":[{"award-number":["82371464"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Natural Science Foundation of China","award":["82171454"],"award-info":[{"award-number":["82171454"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Multidisciplinary Cooperative Diagnosis and Treatment Capacity Project for Major Diseases of Xiangya Hospital, Central South University","award":["z027001"],"award-info":[{"award-number":["z027001"]}]},{"name":"Outstanding Youth Science Fund Project of Hunan Province","award":["2024JJ2096"],"award-info":[{"award-number":["2024JJ2096"]}]},{"name":"Institutions of Higher Learning in Shanghai","award":["Peak Disciplines (Type IV)"],"award-info":[{"award-number":["Peak Disciplines (Type IV)"]}]},{"name":"Huffington Foundation","award":["Huffington Foundation"],"award-info":[{"award-number":["Huffington Foundation"]}],"id":[{"id":"https:\/\/ror.org\/04bcjs591","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Chan Zuckerberg Initiative","award":["Chan Zuckerberg Initiative"],"award-info":[{"award-number":["Chan Zuckerberg Initiative"]}],"id":[{"id":"https:\/\/ror.org\/02qenvm24","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Jan and Dan Duncan Neurological Research Institute","award":["Neurogenetics Chair"],"award-info":[{"award-number":["Neurogenetics Chair"]}],"id":[{"id":"https:\/\/ror.org\/02ea83075","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Netherlands Organisation for Scientific Research","award":["ZonMw Vidi grant 09150172110002"],"award-info":[{"award-number":["ZonMw Vidi grant 09150172110002"]}],"id":[{"id":"https:\/\/ror.org\/04jsz6e67","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>\n                    <jats:italic>SEC16A<\/jats:italic>\n                    encodes a scaffold protein that organizes the endoplasmic reticulum (ER) exit sites, specialized ER subdomains that mediate export of newly synthesized proteins and regulate early secretory pathway steps. The role of\n                    <jats:italic>SEC16A<\/jats:italic>\n                    in human nervous system diseases has not been established yet. Here, we report six individuals with bi-allelic\n                    <jats:italic>SEC16A<\/jats:italic>\n                    variants who presented with early-onset neurological symptoms, including cognitive impairment, motor delays, and seizures. Using\n                    <jats:italic>Drosophila<\/jats:italic>\n                    , we show the\n                    <jats:italic>Sec16<\/jats:italic>\n                    ortholog is essential for normal development and that its loss causes early lethality. Neuron-specific knockdown of\n                    <jats:italic>Sec16<\/jats:italic>\n                    causes neurological phenotypes including locomotor defects, seizure-like bang sensitivity, and impaired synaptic transmission, which can be associated with the clinical features observed in affected individuals. Neurons differentiated from patient-derived induced pluripotent stem cells (iPSCs) carrying\n                    <jats:italic>SEC16A<\/jats:italic>\n                    variants display reduced SEC16A protein, impaired neurite outgrowth and increased excitability, which are rescued in isogenic control neurons when the variants are corrected, consistent with a loss-of-function mechanism. Increased ER stress was observed in both patient iPSC-derived neurons and fly models. In summary, our findings indicate a conserved requirement for\n                    <jats:italic>SEC16A<\/jats:italic>\n                    in neurodevelopment and neuronal function and implicate ER stress as a key cellular phenotype underlying the\n                    <jats:italic>SEC16A<\/jats:italic>\n                    -associated neurodevelopmental disorder.\n                  <\/jats:p>","DOI":"10.1172\/jci199882","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T16:00:26Z","timestamp":1791907226000},"source":"Crossref","is-referenced-by-count":0,"title":["Bi-allelic variants in the secretory pathway gene SEC16A are associated with a neurodevelopmental disorder"],"prefix":"10.1172","author":[{"given":"Mengqi","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowei","family":"Lei","sequence":"additional","affiliation":[{"name":"Institute for Regenerative Medicine, Medical Innovation Centre and State Key Laboratory of Cardiovascular Diseases, Shanghai East Hospital, National Stem Cell Translational Resource Centre & Resource , Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, Xiangya Hospital, Central South University, Changsha, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Xiangya Hospital, Central South University, Changsha, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohei","family":"Nitta","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Mao","sequence":"additional","affiliation":[{"name":"National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Changsha, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenming","family":"Guo","sequence":"additional","affiliation":[{"name":"Institute for Regenerative Medicine, Medical Innovation Centre and State Key Laboratory of Cardiovascular Diseases, Shanghai East Hospital, National Stem Cell Translational Resource Centre & Resource , Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3117-3900","authenticated-orcid":true,"given":"Shenzhao","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingxi","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueyang","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oguz","family":"Kanca","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyi","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute for Regenerative Medicine, Medical Innovation Centre and State Key Laboratory of Cardiovascular Diseases, Shanghai East Hospital, National Stem Cell Translational Resource Centre & Resource , Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, The Affiliated Children's Hospital of Xiangya School of Medicine, Hunan Children's Hospital, Central South University, Changsha, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Neurology, Xiangya Hospital, Central South University, Changsha, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Schot","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serwet","family":"Demirdas","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yolande","family":"van Bever","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjon","family":"van Slegtenhorst","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tahsin Stefan","family":"Barakat","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Bian","sequence":"additional","affiliation":[{"name":"Institute for Regenerative Medicine, Medical Innovation Centre and State Key Laboratory of Cardiovascular Diseases, Shanghai East Hospital, National Stem Cell Translational Resource Centre & Resource , Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugo J.","family":"Bellen","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Long","sequence":"additional","affiliation":[{"name":"Department of Neurology, Xiangya Hospital, Central South University, Changsha, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,10,13]]},"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.jci.org\/articles\/view\/199882\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T16:00:29Z","timestamp":1791907229000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.jci.org\/articles\/view\/199882"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,13]]},"references-count":0,"alternative-id":["10.1172\/JCI199882"],"URL":"https:\/\/doi.org\/10.1172\/jci199882","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,13]]}}}