論文 - 詳細
| RRC ID | 83907 |
|---|---|
| 著者 | Confino S, Wexler Y, Medvetzky A, Elazary Y, Ben-Moshe Z, Reiter J, Dor T, Edvardson S, Prag G, Harel T, Gothilf Y. |
| タイトル | A deleterious variant of INTS1 leads to disrupted sleep-wake cycles. |
| ジャーナル | Dis Model Mech |
| 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. |
| 巻・号 | 17(8) |
| 公開日 | 2024-8-1 |
| DOI | 10.1242/dmm.050746 |
| PII | 361761 |
| PMID | 39189071 |
| PMC | PMC11381918 |
| MeSH | Amino Acid Sequence Animals Child Circadian Rhythm* / genetics DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism Female Humans Larva / genetics Male Pedigree Sleep* / genetics Sleep* / physiology Wakefulness / genetics Wakefulness / physiology Zebrafish* / genetics Zebrafish Proteins / genetics Zebrafish Proteins / metabolism |
| IF | 4.651 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 2 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ゼブラフィッシュ | Tg(gad1b:GFP) |