RARE DISEASE
Familial advanced sleep-phase syndrome
Familial advanced sleep-phase syndrome
Familial advanced sleep-phase syndrome
Synonyms: FASPS
Synonyms: FASPS
Synonyms: FASPS
Drug discovery
23
papers
On emerging therapies
Overview
Familial Advanced Sleep-Phase Syndrome (FASPS) is a rare autosomal dominant circadian rhythm disorder characterized by a lifelong, extreme advancement of sleep-wake cycles (sleep onset ~7:30 PM, wake time ~4:30 AM). It stems from mutations in core circadian genes (e.g., PER2, CK1δ), causing a shortened endogenous circadian period (~22 hours). Key features include stable early melatonin secretion, advanced core body temperature rhythms, and normal sleep quality when allowed to follow innate timing. Over 50% of first-degree relatives are typically affected [1][11][15].
Burden
Complications: Sleep deprivation from forced alignment with conventional schedules, leading to daytime impairment and reduced quality of life [1][2].
Comorbidities: Linked to migraine (in some families) and seasonal affective disorder [1][11].
Social impact: Disruption of evening activities and occupational demands, often requiring lifelong management [2][15].
Therapies
Bright light therapy: Evening exposure (7–9 PM) to delay circadian phase, with limited long-term efficacy [1][6][8].
Behavioral adjustments: Sleep scheduling accommodations to align with social obligations, though adherence is challenging [1][6].
Experimental approaches: Genetic counseling and circadian-targeted interventions under investigation; melatonin and hypnotics lack robust evidence [3][5][9].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
23 drug discovery papers about Familial advanced sleep-phase syndrome. Recent publications:
23 drug discovery papers about Familial advanced sleep-phase syndrome. Recent publications:
categories:
Small molecules
small molecules
2026-05-31 | GAPVD1 regulates CSNK1D-dependent PER2 FASP phosphorylation
The mammalian circadian clock relies on precisely timed transcriptional and post-translational events to generate ∼24-hour rhythms. A key post-translational mechanism is phosphorylation of PER2 by CSNK1D, governed by a phosphoswitch that integrates stabilizing and destabilizing phosphorylation marks at the FASP and Degron sites to control PER2 stability and circadian period. Here, a novel role for the PER complex protein GAPVD1 in regulating CSNK1D-mediated FASP site phosphorylation is revealed. GAPVD1 associates with PER2 and CSNK1D via a distinct helical bundle domain, weakening PER2-CSNK1D association and attenuating PER2 FASP phosphorylation in cells and in vitro. Mechanistically, this helical bundle interacts with the PER2 casein kinase binding domain and is contacted by the adjacent VPS9 region in GAPVD1, providing a structural explanation for how flanking GAPVD1 domains can control access of binding proteins to the helical bundle. Notably, a minimal GAPVD1 helical bundle fragment is sufficient for binding to PER2 and CSNK1D but not for robust attenuation of PER2 FASP phosphorylation, indicating that additional regions of GAPVD1 are required. GAPVD1-mediated inhibition of PER2 FASP phosphorylation also turned out to be independent of the CSNK1D C-terminal tail, pointing to mechanisms such as displacement of PER2 FASP from the CSNK1D active site or allosteric regulation of CSNK1D substrate engagement. Together, these findings identify GAPVD1 as a PER-complex scaffold that modulates the PER2-CSNK1D control node and introduce an additional regulatory layer into the circadian phosphoswitch. A GAPVD1 helical bundle domain binds the PER2 CKBD and CSNK1D to weaken PER2-CSNK1D interaction and attenuate PER2 FASP phosphorylation.
2025-01-22 | Markovian State Models uncover Casein Kinase 1 dynamics that govern circadian period
Circadian rhythms in mammals are tightly regulated through phosphorylation of Period (PER) proteins by Casein Kinase 1 (CK1, subtypes δ and ε). CK1 acts on at least two different regions of PER with opposing effects: phosphorylation of phosphodegron (pD) regions leads to PER degradation, while phosphorylation of the Familial Advanced Sleep Phase (FASP) region leads to PER stabilization. To investigate how substrate selectivity is encoded by the conformational dynamics of CK1, we performed a large set of independent molecular dynamics (MD) simulations of wildtype CK1 and the tau mutant (R178C) that biases kinase activity toward a pD. We used Markovian State Models (MSMs) to integrate the simulations into a single model of the conformational landscape of CK1 and used Gaussian accelerated molecular dynamics (GaMD) to build the first molecular model of CK1 and the unphosphorylated FASP motif. Together, these findings provide a mechanistic view of CK1, establishing how the activation loop acts as a key molecular switch to control substrate selectivity. We show that the tau mutant favors an alternative conformation of the activation loop and significantly accelerates the dynamics of CK1. This reshapes the binding cleft in a way that impairs FASP binding and would ultimately lead to PER destabilization and shorter circadian periods. Finally, we identified an allosteric pocket that could be targeted to bias this molecular switch. Our integrated approach offers a detailed model of CK1's conformational landscape and its relevance to normal, mutant, and druggable circadian timekeeping.
2022-06-26 | PERIOD phosphorylation leads to feedback inhibition of CK1 activity to control circadian period
Summary PERIOD (PER) and Casein Kinase 1δ regulate circadian rhythms through a phosphoswitch that controls PER stability and repressive activity in the molecular clock. CK1δ phosphorylation of the Familial Advanced Sleep Phase (FASP) serine cluster embedded within the Casein Kinase 1 binding domain (CK1BD) of mammalian PER1/2 inhibits its activity on phosphodegrons to stabilize PER and extend circadian period. Here, we show that the phosphorylated FASP region (pFASP) of PER2 directly interacts with and inhibits CK1δ. Co-crystal structures in conjunction with accelerated molecular dynamics simulations reveal how pFASP phosphoserines dock into conserved anion binding sites near the active site of CK1δ. Limiting phosphorylation of the FASP serine cluster reduces product inhibition, decreasing PER2 stability and shortens circadian period in human cells. We found that Drosophila PER also regulates CK1δ via feedback inhibition through the phosphorylated PER-Short domain, revealing a conserved mechanism by which PER phosphorylation near the CK1BD regulates CK1 kinase activity.
2019-06-21 | The Genetic Regulation of Human Sleep-Wake Rhythms and Patterns
The application of forward genetic approaches to heritable human sleep and circadian traits has greatly refined our understanding of these indispensable processes. Familial advanced sleep phase is a circadian condition where affected individuals awaken and sleep significantly earlier compared with unaffected family members but have otherwise normal sleep. Causative genetic variants have led to an in-depth appreciation of the pathways of posttranslational regulation for known circadian proteins to affect the timing of sleep-wake behavior. The homeostatic drive to sleep, which is defined as an increasing propensity to sleep after periods of wakefulness, is altered in natural short sleep subjects who require significantly shorter sleep than conventional sleepers. Investigations into this condition led to the recent identification of a novel sleep gene/mutation, providing the first insight into a pathway regulating sleep need. A better understanding of the molecular regulation of sleep will undoubtedly set the stage for improving therapies for sleep disturbances.
2019-02-01 | Chemical Control of Mammalian Circadian Behavior through Dual Inhibition of Casein Kinase Iα and δ
Circadian rhythms are controlled by transcriptional feedback loops of clock genes and proteins. The stability of clock proteins is regulated by post-translational modification, such as phosphorylation by kinases. In particular, casein kinase I (CKI) phosphorylates the PER protein to regulate proteasomal degradation and nuclear localization. Therefore, CKI inhibition can modulate mammalian circadian rhythms. In the present study, we have developed novel CKIα and CKIδ dual inhibitors by extensive structural modification of N9 and C2 position of longdaysin. We identified NCC007 that showed stronger period effects (0.32 μM for 5 h period lengthening) in a cell-based circadian assay. The following in vitro kinase assay showed that NCC007 inhibited CKIα and CKIδ with an IC50 of 1.8 and 3.6 μM. We further demonstrated that NCC007 lengthened the period of mouse behavioral rhythms in vivo. Thus, NCC007 is a valuable tool compound to control circadian rhythms through CKI inhibition.
small molecules
2026-05-31 | GAPVD1 regulates CSNK1D-dependent PER2 FASP phosphorylation
The mammalian circadian clock relies on precisely timed transcriptional and post-translational events to generate ∼24-hour rhythms. A key post-translational mechanism is phosphorylation of PER2 by CSNK1D, governed by a phosphoswitch that integrates stabilizing and destabilizing phosphorylation marks at the FASP and Degron sites to control PER2 stability and circadian period. Here, a novel role for the PER complex protein GAPVD1 in regulating CSNK1D-mediated FASP site phosphorylation is revealed. GAPVD1 associates with PER2 and CSNK1D via a distinct helical bundle domain, weakening PER2-CSNK1D association and attenuating PER2 FASP phosphorylation in cells and in vitro. Mechanistically, this helical bundle interacts with the PER2 casein kinase binding domain and is contacted by the adjacent VPS9 region in GAPVD1, providing a structural explanation for how flanking GAPVD1 domains can control access of binding proteins to the helical bundle. Notably, a minimal GAPVD1 helical bundle fragment is sufficient for binding to PER2 and CSNK1D but not for robust attenuation of PER2 FASP phosphorylation, indicating that additional regions of GAPVD1 are required. GAPVD1-mediated inhibition of PER2 FASP phosphorylation also turned out to be independent of the CSNK1D C-terminal tail, pointing to mechanisms such as displacement of PER2 FASP from the CSNK1D active site or allosteric regulation of CSNK1D substrate engagement. Together, these findings identify GAPVD1 as a PER-complex scaffold that modulates the PER2-CSNK1D control node and introduce an additional regulatory layer into the circadian phosphoswitch. A GAPVD1 helical bundle domain binds the PER2 CKBD and CSNK1D to weaken PER2-CSNK1D interaction and attenuate PER2 FASP phosphorylation.
2025-01-22 | Markovian State Models uncover Casein Kinase 1 dynamics that govern circadian period
Circadian rhythms in mammals are tightly regulated through phosphorylation of Period (PER) proteins by Casein Kinase 1 (CK1, subtypes δ and ε). CK1 acts on at least two different regions of PER with opposing effects: phosphorylation of phosphodegron (pD) regions leads to PER degradation, while phosphorylation of the Familial Advanced Sleep Phase (FASP) region leads to PER stabilization. To investigate how substrate selectivity is encoded by the conformational dynamics of CK1, we performed a large set of independent molecular dynamics (MD) simulations of wildtype CK1 and the tau mutant (R178C) that biases kinase activity toward a pD. We used Markovian State Models (MSMs) to integrate the simulations into a single model of the conformational landscape of CK1 and used Gaussian accelerated molecular dynamics (GaMD) to build the first molecular model of CK1 and the unphosphorylated FASP motif. Together, these findings provide a mechanistic view of CK1, establishing how the activation loop acts as a key molecular switch to control substrate selectivity. We show that the tau mutant favors an alternative conformation of the activation loop and significantly accelerates the dynamics of CK1. This reshapes the binding cleft in a way that impairs FASP binding and would ultimately lead to PER destabilization and shorter circadian periods. Finally, we identified an allosteric pocket that could be targeted to bias this molecular switch. Our integrated approach offers a detailed model of CK1's conformational landscape and its relevance to normal, mutant, and druggable circadian timekeeping.
2022-06-26 | PERIOD phosphorylation leads to feedback inhibition of CK1 activity to control circadian period
Summary PERIOD (PER) and Casein Kinase 1δ regulate circadian rhythms through a phosphoswitch that controls PER stability and repressive activity in the molecular clock. CK1δ phosphorylation of the Familial Advanced Sleep Phase (FASP) serine cluster embedded within the Casein Kinase 1 binding domain (CK1BD) of mammalian PER1/2 inhibits its activity on phosphodegrons to stabilize PER and extend circadian period. Here, we show that the phosphorylated FASP region (pFASP) of PER2 directly interacts with and inhibits CK1δ. Co-crystal structures in conjunction with accelerated molecular dynamics simulations reveal how pFASP phosphoserines dock into conserved anion binding sites near the active site of CK1δ. Limiting phosphorylation of the FASP serine cluster reduces product inhibition, decreasing PER2 stability and shortens circadian period in human cells. We found that Drosophila PER also regulates CK1δ via feedback inhibition through the phosphorylated PER-Short domain, revealing a conserved mechanism by which PER phosphorylation near the CK1BD regulates CK1 kinase activity.
2019-06-21 | The Genetic Regulation of Human Sleep-Wake Rhythms and Patterns
The application of forward genetic approaches to heritable human sleep and circadian traits has greatly refined our understanding of these indispensable processes. Familial advanced sleep phase is a circadian condition where affected individuals awaken and sleep significantly earlier compared with unaffected family members but have otherwise normal sleep. Causative genetic variants have led to an in-depth appreciation of the pathways of posttranslational regulation for known circadian proteins to affect the timing of sleep-wake behavior. The homeostatic drive to sleep, which is defined as an increasing propensity to sleep after periods of wakefulness, is altered in natural short sleep subjects who require significantly shorter sleep than conventional sleepers. Investigations into this condition led to the recent identification of a novel sleep gene/mutation, providing the first insight into a pathway regulating sleep need. A better understanding of the molecular regulation of sleep will undoubtedly set the stage for improving therapies for sleep disturbances.
2019-02-01 | Chemical Control of Mammalian Circadian Behavior through Dual Inhibition of Casein Kinase Iα and δ
Circadian rhythms are controlled by transcriptional feedback loops of clock genes and proteins. The stability of clock proteins is regulated by post-translational modification, such as phosphorylation by kinases. In particular, casein kinase I (CKI) phosphorylates the PER protein to regulate proteasomal degradation and nuclear localization. Therefore, CKI inhibition can modulate mammalian circadian rhythms. In the present study, we have developed novel CKIα and CKIδ dual inhibitors by extensive structural modification of N9 and C2 position of longdaysin. We identified NCC007 that showed stronger period effects (0.32 μM for 5 h period lengthening) in a cell-based circadian assay. The following in vitro kinase assay showed that NCC007 inhibited CKIα and CKIδ with an IC50 of 1.8 and 3.6 μM. We further demonstrated that NCC007 lengthened the period of mouse behavioral rhythms in vivo. Thus, NCC007 is a valuable tool compound to control circadian rhythms through CKI inhibition.
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