{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T19:57:49Z","timestamp":1784663869825,"version":"3.55.0"},"reference-count":16,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,4,18]],"date-time":"2025-04-18T00:00:00Z","timestamp":1744934400000},"content-version":"vor","delay-in-days":17,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Biallelic variants of <jats:italic>COL18A1<\/jats:italic> cause Knobloch syndrome (KNO), a rare genetic disorder, characterized by oculopathy and structural defects. Recently, several studies have suggested that novel <jats:italic>de novo<\/jats:italic> missense variants in <jats:italic>PAK2<\/jats:italic> may be associated with KNO; however, there are few case reports. This study aimed to investigate a patient with KNO who initially presented with seizures and expand the <jats:italic>PAK2<\/jats:italic> genotype and phenotype spectrum.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This study included a Chinese family with a proband who primarily presented with epilepsy and developmental delay. Whole\u2010exome sequencing and Sanger sequencing were performed to analyze potential variants. Structural modeling was performed to assess the impact of the variant on the protein structure. In\u00a0vitro, a mutant plasmid was constructed and transfected into 293T cells to conduct phosphorylation assays, and phosphorylation levels at Ser141 of PAK2 were assessed. The PAK kinase inhibitor FRAX597 was used to confirm the specificity of the western blot results.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A <jats:italic>de novo<\/jats:italic> variant of <jats:italic>PAK2<\/jats:italic> gene, NM_002577.4: c.1049G&gt;A (p.Arg350Lys) was found in the patient but not in his parents or sister. This variant was found to be located in the kinase domain and may alter the hydrogen\u2010bond network, potentially affecting kinase activity. In\u00a0vitro functional experiments demonstrated that the variant may lead to reduced protein levels. Moreover, Western blot analysis showed a significant decrease in the phosphorylation level at Ser141 compared to the wild\u2010type plasmid, indicating that the variant may lead to decreased PAK2 phosphorylation levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The clinical manifestations in this patient may be associated with a novel <jats:italic>PAK2<\/jats:italic> variant, and the atypical presentation of KNO suggests that PAK2\u2010related KNO may have a broader phenotypic spectrum.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.70099","type":"journal-article","created":{"date-parts":[[2025,4,18]],"date-time":"2025-04-18T07:41:16Z","timestamp":1744962076000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Chinese Family With Knobloch Syndrome Associated With a Novel <i>PAK2<\/i> Variant Leading to Reduced Phosphorylation Levels"],"prefix":"10.1002","volume":"13","author":[{"given":"Liwei","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Neurology Anhui Provincial Children's Hospital\/Children's Hospital of Fudan University (Affiliated Anhui Branch)  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofei","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Neurology Anhui Provincial Children's Hospital\/Children's Hospital of Fudan University (Affiliated Anhui Branch)  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaocui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology Anhui Provincial Children's Hospital\/Children's Hospital of Fudan University (Affiliated Anhui Branch)  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Conglei","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Neurology Anhui Provincial Children's Hospital\/Children's Hospital of Fudan University (Affiliated Anhui Branch)  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0087-7549","authenticated-orcid":false,"given":"Bin","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neurology Anhui Provincial Children's Hospital\/Children's Hospital of Fudan University (Affiliated Anhui Branch)  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,4,18]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddab026"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2014.08.025"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adg7492"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2023.1123784"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12098\u2010023\u201004861\u2010w"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaophthalmol.2016.1073"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M007753200"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.20070"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2016.12.014"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.152.6.1233"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes12101512"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.14578"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.07.061"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.64006"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1080\/13816810701850041"}],"container-title":["Molecular Genetics &amp; Genomic Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.70099","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T13:06:32Z","timestamp":1747314392000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mgg3.70099"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4]]},"references-count":16,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,4]]}},"alternative-id":["10.1002\/mgg3.70099"],"URL":"https:\/\/doi.org\/10.1002\/mgg3.70099","archive":["Portico"],"relation":{},"ISSN":["2324-9269","2324-9269"],"issn-type":[{"value":"2324-9269","type":"print"},{"value":"2324-9269","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4]]},"assertion":[{"value":"2025-01-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70099"}}