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In this study, de novo CTR9 non-synonymous variants (p.(Glu15Asp) and p.(Pro25Arg)) were detected in two unrelated patients with macrocephaly, motor delay, and intellectual disability. A pull-down assay showed that the mutant CTR9 proteins had stronger affinities to the PAF1 protein than the wild-type protein. Functional analyses using zebrafish showed that the knockout of the ctr9 gene caused motor defects and enlargement of the telencephalon, which is homologous to the mammalian cerebrum. The rescue experiment, in which the human CTR9 mutants were introduced into ctr9-knockout zebrafish, failed to maintain the swimming posture of the ctr9-knockout fish, suggesting that the human CTR9 mutant proteins do not function normally in vivo. In addition, the overexpression of human CTR9 mutant mRNA caused telencephalon enlargement in zebrafish larvae, suggesting that the human CTR9 mutant proteins interfered with normal endogenous CTR9 function. We concluded that the two missense variants in CTR9 (p.(Glu15Asp) and p.(Pro25Arg)) cause a new syndrome involving macrocephaly, motor delay and intellectual disability through the loss of the normal function of CTR9 and the inhibition of the normal intrinsic CTR9 function of the contralateral allele.<\/jats:p>","DOI":"10.1093\/hmg\/ddac136","type":"journal-article","created":{"date-parts":[[2022,6,19]],"date-time":"2022-06-19T07:05:35Z","timestamp":1655622335000},"page":"3846-3854","source":"Crossref","is-referenced-by-count":1,"title":["<i>De novo<\/i> non-synonymous CTR9 variants are associated with motor delay and macrocephaly: human genetic and zebrafish experimental evidence"],"prefix":"10.1093","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8122-7180","authenticated-orcid":false,"given":"Hisato","family":"Suzuki","sequence":"first","affiliation":[{"name":"Center for Medical Genetics, Keio University School of Medicine , Tokyo 160-8582, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9664-741X","authenticated-orcid":false,"given":"Kana","family":"Aoki","sequence":"additional","affiliation":[{"name":"Department of Homeostatic Regulation , Division of Cellular and Molecular Biology, Research Institute for Microbial Diseases, , Suita, Osaka 565-0871, Japan"},{"name":"Osaka University , Division of Cellular and Molecular Biology, Research Institute for Microbial Diseases, , Suita, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenji","family":"Kurosawa","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Kanagawa Children\u2019s Medical Center , Yokohama, Kanagawa 232-8555, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuo","family":"Imagawa","sequence":"additional","affiliation":[{"name":"Department of Child Health , Faculty of Medicine, , Ibaraki 305-8575, Japan"},{"name":"University of Tsukuba , Faculty of Medicine, , Ibaraki 305-8575, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatsuyuki","family":"Ohto","sequence":"additional","affiliation":[{"name":"Department of Child Health , Faculty of Medicine, , Ibaraki 305-8575, Japan"},{"name":"University of Tsukuba , Faculty of Medicine, , Ibaraki 305-8575, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mamiko","family":"Yamada","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics, Keio University School of Medicine , Tokyo 160-8582, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiki","family":"Takenouchi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Keio University School of Medicine , Tokyo 160-8582, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenjiro","family":"Kosaki","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics, Keio University School of Medicine , Tokyo 160-8582, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tohru","family":"Ishitani","sequence":"additional","affiliation":[{"name":"Department of Homeostatic Regulation , Division of Cellular and Molecular Biology, Research Institute for Microbial Diseases, , Suita, Osaka 565-0871, Japan"},{"name":"Osaka University , Division of Cellular and Molecular Biology, Research Institute for Microbial Diseases, , Suita, Osaka 565-0871, Japan"},{"name":"Center for Infectious Disease Education and Research (CiDER), Osaka University , Suita, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,6,18]]},"reference":[{"key":"2022111201002577500_ref1","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.bbagrm.2010.01.001","article-title":"The Paf1 complex: platform or player in RNA polymerase II transcription?","volume":"1799","author":"Jaehning","year":"2010","journal-title":"Biochim. 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