De novo non-synonymous CTR9 variants are associated with motor delay and macrocephaly: human genetic and zebrafish experimental evidence
De novo non-synonymous CTR9 variants are associated with motor delay and macrocephaly: human genetic and zebrafish experimental evidence
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从头非同义 CTR9 变异与运动迟缓和大头畸形相关：人类遗传和斑马鱼实验证据
DOI：
10.1093/hmg/ddac136
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发表时间：
2022
影响因子：
3.5
通讯作者：
Ishitani Tohru
中科院分区：
文献类型：
--
作者：
Suzuki Hisato;Aoki Kana;Kurosawa Kenji;Imagawa Kazuo;Ohto Tatsuyuki;Yamada Mamiko;Takenouchi Toshiki;Kosaki Kenjiro;Ishitani Tohru
CTR 9是形成PAF 1复合物的五个基因之一，与RNA聚合酶II结合，在转录延伸和转录偶联的组蛋白修饰（包括组蛋白H3 K4 me 3和H3 K36 me 3）中起关键作用。在这项研究中，从头CTR 9非同义变体（p.（Glu 15 Asp）和p.（Pro25 Arg））在两个不相关的患有大头畸形、运动延迟和智力残疾的患者中检测到。pull-down分析表明，突变CTR 9蛋白与PAF 1蛋白的亲和力比野生型蛋白强。利用斑马鱼进行的功能分析表明，tr 9基因的敲除导致了运动缺陷和端脑的扩大，这与哺乳动物的大脑同源。将人CTR 9突变体导入ctr 9敲除斑马鱼的拯救实验中，未能维持ctr 9敲除鱼的游泳姿势，表明人CTR 9突变蛋白在体内不能正常发挥功能。此外，人类CTR 9突变体mRNA的过表达导致斑马鱼幼鱼端脑增大，表明人类CTR 9突变体蛋白干扰了正常的内源性CTR 9功能。我们得出结论，CTR 9中的两个错义变体（p.（Glu 15 Asp）和p.（Pro25 Arg））通过对侧等位基因的正常固有CTR 9功能的抑制和CTR 9正常功能的丧失，导致一种新的综合征，包括大头畸形、运动迟缓和智力残疾。
CTR9is 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 CTR9non-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 thectr9gene caused motor defects and enlargement of the telencephalon, which is homologous to the mammalian cerebrum. The rescue experiment, in which the humanCTR9mutants were introduced intoctr9-knockout zebrafish, failed to maintain the swimming posture of thectr9-knockout fish, suggesting that the human CTR9 mutant proteins do not function normallyin vivo. In addition, the overexpression of humanCTR9mutant 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 inCTR9(p.(Glu15Asp) and p.(Pro25Arg)) cause a new syndrome involving macrocephaly, motor delay and intellectual disability through the loss of the normal function ofCTR9and the inhibition of the normal intrinsicCTR9function of the contralateral allele.