{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T23:32:51Z","timestamp":1790379171841,"version":"4.1.0"},"reference-count":18,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T00:00:00Z","timestamp":1753747200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T00:00:00Z","timestamp":1753747200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100023674","name":"Deanship of Scientific Research, King Khalid University","doi-asserted-by":"publisher","award":["RGP2\/604\/45"],"award-info":[{"award-number":["RGP2\/604\/45"]}],"id":[{"id":"10.13039\/501100023674","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2026,2]]},"abstract":"ABSTRACT<\/jats:title>\n \n Neurodevelopmental disorders arising from mutations in RNA\u2010processing factors are increasingly recognized but remain mechanistically underexplored. Here, we identify that variant (c.485A>C; p.Lys137Gln) in\n DDX39A<\/jats:italic>\n in a 7\u2010month\u2010old proband presenting with global developmental delay, microcephaly, seizures, hypotonia, and brain atrophy with corpus callosum thinning.\n DDX39A<\/jats:italic>\n encodes a DEAD\u2010box RNA helicase essential for mRNA splicing and export via the TREX complex. Functional studies in proband\u2010derived fibroblasts revealed that while transcript and protein levels of DDX39A\u2010K137Q were unaffected, the mutant protein displayed aberrant nuclear clumping and failed to interact with the TREX component THOC1. Structural modeling demonstrated that Lys137 mediates critical inter\u2010 and intra\u2010molecular interactions, which are disrupted by the K137Q substitution. This loss destabilizes the DDX39A\u2010THOC1 interface, impairing TREX complex integrity. The mutant cells exhibited severe nuclear morphological abnormalities, disrupted nuclear lamina organization, and increased cell death. Transcriptomic network analysis and gene ontology revealed enrichment of DDX39A interactions in mRNA export, splicing, and nucleocytoplasmic transport\u2014functions essential for neuronal development. Temporal and regional brain expression data showed that DDX39A is highly expressed during early postnatal life and across multiple brain regions, indicating its importance in early brain maturation. Our findings establish DDX39A\u2010K137Q as a pathogenic variant that impairs nuclear RNA processing and structural homeostasis, leading to a severe neurodegenerative phenotype. This study identifies the role of RNA helicases in neurodevelopment and explores\n DDX39A<\/jats:italic>\n as a novel gene implicated in pediatric neurodegenerative disease.\n <\/jats:p>","DOI":"10.1111\/cge.70033","type":"journal-article","created":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T08:19:05Z","timestamp":1753777145000},"page":"243-254","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pathogenic\n \n DDX39A<\/i>\n <\/scp>\n Variant Disrupts Nuclear Homeostasis and Causes an Early\u2010Onset Neurodegenerative Disorder With Cerebral Atrophy"],"prefix":"10.1111","volume":"109","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0796-5238","authenticated-orcid":false,"given":"S. Rehan","family":"Ahmad","sequence":"first","affiliation":[{"name":"Hiralal Mazumdar Memorial College for Women West Bengal State University Kolkata West Bengal India"}],"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 Mushait Campus King Khalid University (KKU) Abha Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natchimuthu","family":"Vijayakumar","sequence":"additional","affiliation":[{"name":"M.Kumarasamy College of Engineering Karur Tamil Nadu India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5414-106X","authenticated-orcid":false,"given":"Anupriya","family":"Kumari","sequence":"additional","affiliation":[{"name":"School of Education Adamas University Kolkata West Bengal India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,29]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.02.011"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13146"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2548"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23557"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2016.50"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0043804"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1898610"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2832-5"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2020.02.036"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2015.07.004"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11922"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.07.033"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2015.05.021"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaf035"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3154"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2019.07.010"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.62359"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20160010"}],"container-title":["Clinical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.70033","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cge.70033","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.70033","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:42:08Z","timestamp":1776645728000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cge.70033"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,29]]},"references-count":18,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,2]]}},"alternative-id":["10.1111\/cge.70033"],"URL":"https:\/\/doi.org\/10.1111\/cge.70033","archive":["Portico"],"relation":{},"ISSN":["0009-9163","1399-0004"],"issn-type":[{"value":"0009-9163","type":"print"},{"value":"1399-0004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,29]]},"assertion":[{"value":"2025-06-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}