PUBLICATION
A deleterious variant of INTS1 leads to disrupted sleep-wake cycles
- Authors
- Confino, S., Wexler, Y., Medvetzky, A., Elazary, Y., Ben-Moshe, Z., Reiter, J., Dor, T., Edvardson, S., Prag, G., Harel, T., Gothilf, Y.
- ID
- ZDB-PUB-240828-5
- Date
- 2024
- Source
- Disease models & mechanisms 17(8): (Journal)
- Registered Authors
- Gothilf, Yoav
- Keywords
- Circadian clock, Dopamine β-hydroxylase (DBH), INTS1, Integrator complex, Sleep, Zebrafish
- MeSH Terms
-
- Amino Acid Sequence
- Animals
- Child
- Circadian Rhythm*/genetics
- Female
- Humans
- Larva/genetics
- Male
- Pedigree
- Sleep*/genetics
- Sleep*/physiology
- Wakefulness/genetics
- Wakefulness/physiology
- Zebrafish*/genetics
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 39189071 Full text @ Dis. Model. Mech.
Citation
Confino, S., Wexler, Y., Medvetzky, A., Elazary, Y., Ben-Moshe, Z., Reiter, J., Dor, T., Edvardson, S., Prag, G., Harel, T., Gothilf, Y. (2024) A deleterious variant of INTS1 leads to disrupted sleep-wake cycles. Disease models & mechanisms. 17(8):.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping