PUBLICATION
A Zebrafish Model for a Rare Genetic Disease Reveals a Conserved Role for FBXL3 in the Circadian Clock System
- Authors
- Confino, S., Dor, T., Tovin, A., Wexler, Y., Ben-Moshe Livne, Z., Kolker, M., Pisanty, O., Park, S.K., Geyer, N., Reiter, J., Edvardson, S., Mor-Shaked, H., Elpeleg, O., Vallone, D., Appelbaum, L., Foulkes, N.S., Gothilf, Y.
- ID
- ZDB-PUB-220227-9
- Date
- 2022
- Source
- International Journal of Molecular Sciences 23(4): (Journal)
- Registered Authors
- Appelbaum, Lior, Foulkes, Nicholas-Simon, Gothilf, Yoav, Vallone, Daniela
- Keywords
- FBXL3, circadian clock, rare genetic disease, zebrafish
- MeSH Terms
-
- Animals
- Circadian Clocks/genetics*
- Circadian Rhythm/genetics
- F-Box Proteins/genetics*
- Genetic Diseases, Inborn/genetics*
- Humans
- Intellectual Disability/genetics
- Mammals/genetics
- Models, Animal
- Mutation/genetics
- Rare Diseases/genetics*
- Zebrafish/genetics*
- PubMed
- 35216494 Full text @ Int. J. Mol. Sci.
Citation
Confino, S., Dor, T., Tovin, A., Wexler, Y., Ben-Moshe Livne, Z., Kolker, M., Pisanty, O., Park, S.K., Geyer, N., Reiter, J., Edvardson, S., Mor-Shaked, H., Elpeleg, O., Vallone, D., Appelbaum, L., Foulkes, N.S., Gothilf, Y. (2022) A Zebrafish Model for a Rare Genetic Disease Reveals a Conserved Role for FBXL3 in the Circadian Clock System. International Journal of Molecular Sciences. 23(4):.
Abstract
The circadian clock, which drives a wide range of bodily rhythms in synchrony with the day-night cycle, is based on a molecular oscillator that ticks with a period of approximately 24 h. Timed proteasomal degradation of clock components is central to the fine-tuning of the oscillator's period. FBXL3 is a protein that functions as a substrate-recognition factor in the E3 ubiquitin ligase complex, and was originally shown in mice to mediate degradation of CRY proteins and thus contribute to the mammalian circadian clock mechanism. By exome sequencing, we have identified a FBXL3 mutation in patients with syndromic developmental delay accompanied by morphological abnormalities and intellectual disability, albeit with a normal sleep pattern. We have investigated the function of FBXL3 in the zebrafish, an excellent model to study both vertebrate development and circadian clock function and, like humans, a diurnal species. Loss of fbxl3a function in zebrafish led to disruption of circadian rhythms of promoter activity and mRNA expression as well as locomotor activity and sleep-wake cycles. However, unlike humans, no morphological effects were evident. These findings point to an evolutionary conserved role for FBXL3 in the circadian clock system across vertebrates and to the acquisition of developmental roles in humans.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping