{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T01:29:39Z","timestamp":1792114179740,"version":"4.4.0"},"reference-count":13,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T00:00:00Z","timestamp":1752019200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T00:00:00Z","timestamp":1752019200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100007446","name":"King Khalid University","doi-asserted-by":"publisher","award":["RGP2\/257\/45"],"award-info":[{"award-number":["RGP2\/257\/45"]}],"id":[{"id":"10.13039\/501100007446","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Autophagy is a critical cellular process for maintaining proteostasis and neuronal health. Disruption of this pathway is increasingly recognized in pediatric neurodegenerative disorders. Here, we study a novel previously uncharacterized homozygous and autosomal recessive missense variant, c.1372G&gt;C (p.Gly433Ala), in the autophagy gene ATG2A, identified in a 3\u2010year\u2010old female proband presenting with developmental regression, seizures, cerebellar ataxia, and MRI\u2010confirmed diffuse cerebral and cerebellar atrophy. The affected residue, Gly433, is evolutionarily conserved across eukaryotes and predicted to be structurally and functionally critical. Computational modeling and molecular dynamics simulations revealed that the G433A substitution induces local \u03b2\u2010sheet extension, increased protein flexibility, higher aggregation propensity, and global structural destabilization. Proband\u2010derived fibroblasts expressing ATG2A\u2010G433A showed normal transcript and protein levels, but exhibited mislocalization of ATG2A to the cytosol, reduced colocalization with LC3B, loss of autophagosome formation, and a marked increase in protein aggregates. Proteotoxic stress was further evidenced by significant accumulation of Proteostat\u2010 and SQSTM1\u2010positive granules. Additionally, transcript levels of unfolded protein response markers (GRP78, PERK, ATF4, and CHOP) were significantly upregulated, suggesting increased ER stress signaling. Cell cycle analysis revealed a substantial increase in cell death in proband fibroblasts. Overall, our findings identify ATG2A as a potentially novel disease gene and its G433A variant as a pathogenic substitution that disrupts autophagy and proteostasis, driving neurodegeneration via aggregation\u2010prone misfolding and autophagy failure. This work depicts the first clinical spectrum of ATG2A\u2010related neurodegenerative disorders and highlights the importance of autophagy maintenance in pediatric neurodevelopmental processes.<\/jats:p>","DOI":"10.1111\/cge.70019","type":"journal-article","created":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T13:35:59Z","timestamp":1752068159000},"page":"60-67","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["An Unstable\n                    <scp>ATG2A<\/scp>\n                    Variant Causes a Neurodegenerative Disorder via Impaired Autophagy and Proteotoxic Stress in Brain Atrophy"],"prefix":"10.1111","volume":"109","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0796-5238","authenticated-orcid":false,"given":"S.","family":"Rehan Ahmad","sequence":"first","affiliation":[{"name":"Hiralal Mazumdar Memorial College for Women, West Bengal State University  Kolkata West Bengal India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md.","family":"Zeyaullah","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Science College of Applied Medical Sciences, Khamis Mushayt Campus, King Khalid University (KKU)  Abha Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9433-1913","authenticated-orcid":false,"given":"Abdullah M.","family":"AlShahrani","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Science College of Applied Medical Sciences, Khamis Mushayt Campus, King Khalid University (KKU)  Abha Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danish","family":"Qavi","sequence":"additional","affiliation":[{"name":"Department of Neurology Yale University  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdelrhman A. G.","family":"Altijani","sequence":"additional","affiliation":[{"name":"Department of Public Health, College of Applied Medical Sciences Khamis Mushayt Campus, King Khalid University (KKU)  Abha Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Suhail","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Public Health, College of Applied Medical Sciences Khamis Mushayt Campus, King Khalid University (KKU)  Abha Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khursheed","family":"Muzammil","sequence":"additional","affiliation":[{"name":"Department of Public Health, College of Applied Medical Sciences Khamis Mushayt Campus, King Khalid University (KKU)  Abha Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,9]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3961"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-02840-8"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2562"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.01.028"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2014.204"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.45777"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-019-0203-4"},{"issue":"6","key":"e_1_2_9_9_1","article-title":"Insights Into Autophagosome Biogenesis From Structural and Biochemical Analyses of the ATG2A\u2013WIPI4 Complex","volume":"118","author":"Chowdhury S.","year":"2018","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.12245"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/1873-3468.12901"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0962-8924(00)01852-3"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2017.99"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2024.2405956"}],"container-title":["Clinical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.70019","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cge.70019","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.70019","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T09:02:39Z","timestamp":1779786159000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cge.70019"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,9]]},"references-count":13,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1111\/cge.70019"],"URL":"https:\/\/doi.org\/10.1111\/cge.70019","archive":["Portico"],"relation":{},"ISSN":["0009-9163","1399-0004"],"issn-type":[{"value":"0009-9163","type":"print"},{"value":"1399-0004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,9]]},"assertion":[{"value":"2025-05-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}