A deleterious variant of INTS1 leads to disrupted sleep-wake cycles.

IF 4 3区 医学 Q2 CELL BIOLOGY Disease Models & Mechanisms Pub Date : 2024-08-01 Epub Date: 2024-08-27 DOI:10.1242/dmm.050746
Shir Confino, Yair Wexler, Adar Medvetzky, Yotam Elazary, Zohar Ben-Moshe, Joel Reiter, Talya Dor, Simon Edvardson, Gali Prag, Tamar Harel, Yoav Gothilf
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Abstract

Sleep disturbances are common among children with neurodevelopmental disorders. Here, we report a syndrome characterized by prenatal microcephaly, intellectual disability and severe disruption of sleep-wake cycles in a consanguineous family. Exome sequencing revealed homozygous variants (c.5224G>A and c.6506G>T) leading to the missense mutations E1742K and G2169V in integrator complex subunit 1 (INTS1), the core subunit of the Integrator complex. Conservation and structural analyses suggest that G2169V has a minor impact on the structure and function of the complex, while E1742K significantly alters a negatively charged conserved patch on the surface of the protein. The severe sleep-wake cycles disruption in human carriers highlights a new aspect of Integrator complex impairment. To further study INTS1 pathogenicity, we generated Ints1-deficient zebrafish lines. Mutant zebrafish larvae displayed abnormal circadian rhythms of locomotor activity and sleep, as is the case with the affected humans. Furthermore, Ints1-deficent larvae exhibited elevated levels of dopamine β-hydroxylase (dbh) mRNA in the locus coeruleus, a wakefulness-inducing brainstem center. Altogether, these findings suggest a significant, likely indirect, effect of INTS1 and the Integrator complex on maintaining circadian rhythms of locomotor activity and sleep homeostasis across vertebrates.

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INTS1的有害变体会导致睡眠-觉醒周期紊乱。
睡眠障碍在患有神经发育障碍的儿童中很常见。在此,我们报告了一个近亲结婚家庭中以产前小头畸形、智力障碍和睡眠-觉醒周期严重紊乱为特征的综合征。外显子组测序发现了同源变异(c.5224G>A 和 c.6506G>T),导致整合器复合体核心亚基整合器复合体亚基 1(INTS1)发生错义突变 E1742K 和 G2169V。保守性和结构分析表明,G2169V 对该复合体的结构和功能影响较小,而 E1742K 则显著改变了蛋白质表面的一个带负电的保守斑块。人类携带者严重的睡眠-觉醒周期紊乱凸显了整合子复合体损伤的一个新方面。为了进一步研究 INTS1 的致病性,我们培育了 Ints1 基因缺陷斑马鱼品系。突变斑马鱼幼体表现出异常的运动和睡眠昼夜节律,与受影响的人类一样。此外,Ints1缺陷斑马鱼幼体的多巴胺β-羟化酶(dbh)mRNA水平升高,而多巴胺β-羟化酶是脑干的一个诱导觉醒的中枢。总之,这些研究结果表明,INTS1 和整合子复合体对维持脊椎动物运动活动的昼夜节律和睡眠平衡有重要影响,但这种影响可能是间接的。
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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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