{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T05:00:19Z","timestamp":1790485219369,"version":"4.1.0"},"reference-count":40,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2018,1,24]],"date-time":"2018-01-24T00:00:00Z","timestamp":1516752000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81471163"],"award-info":[{"award-number":["81471163"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81701441"],"award-info":[{"award-number":["81701441"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81771584"],"award-info":[{"award-number":["81771584"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2018,5]]},"abstract":"Summary<\/jats:title>Aim<\/jats:title>Neural tube defects (NTD<\/jats:styled-content>s) are birth defects of the nervous system and are the second most frequent cause of birth defects worldwide. The etiology of NTD<\/jats:styled-content>s is complicated and involves both genetic and environmental factors. CASP<\/jats:styled-content>9 is an initiator caspase in the intrinsic apoptosis pathway, which in Casp9<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice has been shown to result in NTD<\/jats:styled-content>s because of decreased apoptosis. The aim of this study was to evaluate the potential genetic contribution of the CASP<\/jats:styled-content>9<\/jats:italic> gene in human NTD<\/jats:styled-content>s.<\/jats:p><\/jats:sec>Methods<\/jats:title>High\u2010throughput sequencing was performed to screen genetic variants of CASP<\/jats:styled-content>9<\/jats:italic> genes in 355 NTD<\/jats:styled-content> cases and 225 matched controls. Apoptosis\u2010relevant assays were performed on transiently transfected E9 neuroepithelial cells or human embryonic kidney 293T cells, to determine the functional characteristics of NTD<\/jats:styled-content>\u2010specific rare variants under complete or low folic acid (FA) status.<\/jats:p><\/jats:sec>Results<\/jats:title>We found significant expression of CASP<\/jats:styled-content>9<\/jats:italic> rare variants in NTD<\/jats:styled-content>s and identified 4 NTD<\/jats:styled-content>\u2010specific missense variants. Functional assays demonstrated that a p.Y251C variant attenuates apoptosis by reducing CASP<\/jats:styled-content>9 protein expression and decreasing activity of the intrinsic apoptosis pathway. From this, we conclude that this variant may represent a loss\u2010of\u2010function mutation. A 4\u2010time recurrent p.R191G variant did not affect intrinsic apoptosis in complete medium, while it completely inhibited apoptosis induced by low FA medium.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>Our findings identify a genetic link for apoptosis in human NTD<\/jats:styled-content>s and highlight the effect of gene\u2010environment interactions in a complex disease.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.12797","type":"journal-article","created":{"date-parts":[[2018,1,25]],"date-time":"2018-01-25T00:12:41Z","timestamp":1516839161000},"page":"394-403","source":"Crossref","is-referenced-by-count":13,"title":["Genetic screening and functional analysis of CASP<\/scp>9<\/i> mutations in a Chinese cohort with neural tube defects"],"prefix":"10.1111","volume":"24","author":[{"given":"Xiao\u2010Zhen","family":"Liu","sequence":"first","affiliation":[{"name":"Beijing Municipal Key Laboratory of Child Development and Nutriomics Capital Institute of Pediatrics Beijing 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