期刊
HUMAN MOLECULAR GENETICS
卷 31, 期 22, 页码 3846-3854出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddac136
关键词
-
资金
- Takeda Foundation
- Mitsubishi Foundation
- Kawano Foundation
- Daiichi Sankyo Foundation
- Japan Agency for Medical Research and Development [JP 20ek0109484, JP21ek0109549]
- [20H05365]
- [20K21502]
- [21H05287]
- [19H03412]
- [19H03413]
- [19H03414]
- [19H03415]
- [19H03416]
- [19H03417]
- [19H03418]
- [19H03419]
- [22H02820]
- [22K15104]
- [21J01076]
CTR9 gene mutations are associated with macrocephaly, motor delay, and intellectual disability. The mutant proteins showed stronger affinity to PAF1 protein, and knockout of ctr9 gene in zebrafish resulted in motor defects and enlargement of the telencephalon. Rescue experiments failed to restore normal function, and overexpression of human CTR9 mutant mRNA caused enlargement of telencephalon in zebrafish larvae.
CTR9 is one of five genes that form the PAF1 complex, which binds to RNA polymerase II and plays critical roles in transcriptional elongation and transcription-coupled histone modifications including histones H3K4me3 and H3K36me3. 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.
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