整合子复合物是一种多亚基蛋白质复合物,可调节RNA聚合酶II(RNAPII)转录的新生RNA的加工,包括小核RNA,增强子RNA,端粒RNA,病毒RNA,和蛋白质编码mRNA。整合子亚基11(INTS11)是裂解新生RNA的催化亚基,但是,到目前为止,该亚基的突变与人类疾病无关。这里,我们描述了来自INTS11中具有双等位基因变异的10个无关家族的15个个体,这些个体具有全球发育和语言延迟,智力残疾,运动发育受损,和脑萎缩.与人类观察一致,我们发现,INTS11的果蝇直系同源dIntS11是必不可少的,并在幼虫和成虫阶段的一部分神经元和大多数神经胶质细胞中在中枢神经系统中表达。以果蝇为模型,我们调查了7种变异的效果.我们发现两个(p。Arg17Leu和p.His414Tyr)未能挽救无效突变体的杀伤力,表明它们是强烈的功能丧失变体。此外,我们发现了五个变体(p。Gly55Ser,p.Leu138Phe,p.Lys396Glu,p.Val517Met,和p.Ile553Glu)救援致死性,但导致寿命缩短和爆炸敏感性并影响运动活动,表明它们是部分功能丧失的变体。总之,我们的结果提供了令人信服的证据,证明整合子RNA内切核酸酶的完整性对大脑发育至关重要.
The Integrator complex is a multi-subunit protein complex that regulates the processing of nascent RNAs transcribed by RNA polymerase II (RNAPII), including small nuclear RNAs, enhancer RNAs, telomeric RNAs, viral RNAs, and protein-coding mRNAs. Integrator subunit 11 (
INTS11) is the catalytic subunit that cleaves nascent RNAs, but, to date, mutations in this subunit have not been linked to human disease. Here, we describe 15 individuals from 10 unrelated families with bi-allelic variants in
INTS11 who present with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy. Consistent with human observations, we find that the fly ortholog of
INTS11, dIntS11, is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages. Using Drosophila as a model, we investigated the effect of seven variants. We found that two (p.Arg17Leu and p.His414Tyr) fail to rescue the lethality of null mutants, indicating that they are strong loss-of-function variants. Furthermore, we found that five variants (p.Gly55Ser, p.Leu138Phe, p.Lys396Glu, p.Val517Met, and p.Ile553Glu) rescue lethality but cause a shortened lifespan and bang sensitivity and affect locomotor activity, indicating that they are partial loss-of-function variants. Altogether, our results provide compelling evidence that integrity of the Integrator RNA endonuclease is critical for brain development.