{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T14:05:15Z","timestamp":1784729115065,"version":"3.55.0"},"reference-count":33,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2024,4,22]],"date-time":"2024-04-22T00:00:00Z","timestamp":1713744000000},"content-version":"vor","delay-in-days":21,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:italic>NKAP<\/jats:italic> mutations are associated with Hackmann\u2010Di Donato\u2010type X\u2010linked syndromic intellectual developmental disorder (MRXSHD, MIM: #301039). Here, we elucidate the potential prenatal manifestation of <jats:italic>NKAP<\/jats:italic> mutation\u2010associated disorder for the first time, alongside revealing the relationship between <jats:italic>NKAP<\/jats:italic> mutations and congenital heart defect (CHD) in the Chinese population. An <jats:italic>NKAP<\/jats:italic> mutation (NM_024528.4: c.988C&gt;T, p.Arg330Cys) was identified in two foetuses presenting with CHD. Subsequent mechanistic exploration revealed a marked downregulation of <jats:italic>NKAP<\/jats:italic> transcription within HEK293T cells transfected with <jats:italic>NKAP<\/jats:italic> p.R330C. However, no significant change was observed at the protein level. Moreover, the mutation led to a dysregulation in the transcription of genes associated with cardiac morphogenesis, such as <jats:italic>DHRS3<\/jats:italic>, <jats:italic>DNAH11<\/jats:italic> and <jats:italic>JAG1<\/jats:italic>. Additionally, our research determined that <jats:italic>NKAP<\/jats:italic> p.R330C affected Nkap protein intra\u2010nuclear distribution, and binding with Hdac3. Summarily, our study strengthens <jats:italic>NKAP<\/jats:italic> mutations as a cause of CHD and prompts the reclassification of <jats:italic>NKAP<\/jats:italic> p.R330C as likely pathogenic, thereby establishing a prospective prenatal phenotypic spectrum that provides new insight into the prenatal diagnosis of CHD. Our findings also provide evidence of <jats:italic>NKAP<\/jats:italic> p.R330C pathogenicity and demonstrate the potential mechanism by which p.R330C dysregulates cardiac developmental gene transcription by altering Nkap intra\u2010nuclear distribution and obstructing the interaction between Nkap and Hdac3, thereby leading to CHD.<\/jats:p>","DOI":"10.1111\/jcmm.18305","type":"journal-article","created":{"date-parts":[[2024,4,22]],"date-time":"2024-04-22T12:39:39Z","timestamp":1713789579000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["From phenotype to mechanism: Prenatal spectrum of <scp><i>NKAP<\/i><\/scp> mutation\u2010related disorder and its pathogenesis inducing congenital heart disease"],"prefix":"10.1111","volume":"28","author":[{"given":"Xiayuan","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory Jinhua Maternal and Child Health Care Hospital  Jinhua Zhejiang China"},{"name":"Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology Women's Hospital, School of Medicine Zhejiang University  Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengcheng","family":"Gao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Digital Technology in Medical Diagnostics of Zhejiang Province Dian Diagnostics Group Co., Ltd.  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