Casein Kinase Iδ Mutations in Familial Migraine and Advanced Sleep Phase

Brennan, K. C.; Bates, Emily A.; Shapiro, Robert E.; Zyuzin, Jekaterina; Hallows, William C.; Huang, Yong; Lee, Hsien Yang; Jones, Christopher R.; Fu, Ying Hui; Charles, Andrew; Ptáček, Louis J.

doi:10.1126/scitranslmed.3005784

Cited by 183 publications

(175 citation statements)

References 48 publications

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“…By using a human genetics strategy and studying families with Mendelian circadian phenotypes, we have identified a growing list of clock-gene mutations causing ) that alter the kinase activity 32,36 . Recently, we have reported that the human PER3 protein is destabilized by a mutation affecting two amino acids (P415A H417R) 33 .…”

Section: Instructions For Reviewing Your Article Proofmentioning

confidence: 99%

The intricate dance of post-translational modifications in the rhythm of life

Hirano

Ptáček

2016

Nat Struct Mol Biol

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Section: Instructions For Reviewing Your Article Proofmentioning

confidence: 99%

The intricate dance of post-translational modifications in the rhythm of life

Hirano

Ptáček

2016

Nat Struct Mol Biol

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“…We previously identified mutations in core clock genes that cause FASP by linkage analysis/positional cloning (16) and candidate gene sequencing (17,18). Here we identify two rare missense variants in PER3 (PER3-P415A/H417R) that cause FASP and are associated with elevated Beck Depression Inventory (BDI) and seasonality scores.…”

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confidence: 99%

A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait

Zhang

Hirano

Hsu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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In humans, the connection between sleep and mood has long been recognized, although direct molecular evidence is lacking. We identified two rare variants in the circadian clock gene PERIOD3 (PER3-P415A/H417R) in humans with familial advanced sleep phase accompanied by higher Beck Depression Inventory and seasonality scores. hPER3-P415A/H417R transgenic mice showed an altered circadian period under constant light and exhibited phase shifts of the sleep-wake cycle in a short light period (photoperiod) paradigm. Molecular characterization revealed that the rare variants destabilized PER3 and failed to stabilize PERIOD1/2 proteins, which play critical roles in circadian timing. Although hPER3-P415A/H417R-Tg mice showed a mild depression-like phenotype, Per3 knockout mice demonstrated consistent depression-like behavior, particularly when studied under a short photoperiod, supporting a possible role for PER3 in mood regulation. These findings suggest that PER3 may be a nexus for sleep and mood regulation while fine-tuning these processes to adapt to seasonal changes. I n human populations, alterations in circadian timing can result in mood-related problems (1). An example of this is seasonal affective disorder, also known as "winter depression," which is among the most common mood disorders, with a reported prevalence of 1.5-9%, depending on latitude (2). In addition, shift work has been suggested as a risk factor for major depressive disorder (3), and depression severity correlates with the degree of circadian misalignment (4, 5). A number of genetic variants in core clock genes have been reported as statistically associated with mood disorders, including seasonal affective disorder and major depressive disorder (6-14), but to date none has been causally related with an understanding of specific molecular links.Familial advanced sleep phase (FASP) is a human behavioral phenotype defined by early sleep time and early morning awakening (15). We previously identified mutations in core clock genes that cause FASP by linkage analysis/positional cloning (16) and candidate gene sequencing (17, 18). Here we identify two rare missense variants in PER3 (PER3-P415A/H417R) that cause FASP and are associated with elevated Beck Depression Inventory (BDI) and seasonality scores. Transgenic mice carrying human PER3-P415A/H417R exhibit delayed phase in a short photoperiod and a lengthened period of wheel-running rhythms in constant light. At a molecular level, the rare variants lead to decreased PER3 protein levels, likely due to decreased protein stability. Moreover, we found that PER3-P415A/H417R can exert effects on the clock (at least in part) by reducing its stabilizing effect on PER1 and PER2. Although hPER3-P415A/H417R transgenic mice display mild measures of depression-like phenotype, Per3 −/− mice exhibit consistent depression-like behaviors in multiple tests. The differences are particularly evident in short photoperiods, implying a role for PER3 in mood regulation. Taken together, these results support a role for PER3 in ...

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“…One study identified a dominant, fully penetrant frameshift mutation in the potassium two pore domain channel subfamily K member 18 (KCNK18) gene that co-segregated with migraine with aura in a large multigenerational family (112), suggesting ion channel dysfunction may contribute to migraine susceptibility. Another study reported missense mutations in the casein kinase 1-delta (CSNK1D) gene cosegregated with the presence of migraine and a rare sleep disorder in two unrelated families (113). Animal experiments in both studies showed the dysfunctional gene products may reduce the threshold for cortical spreading depression, consistent with current knowledge on migraine pathophysiology.…”

Section: Monogenic Migraine Syndromessupporting

confidence: 62%

Integrating Genome-Wide Association and Blood Genomic Profiling Data to Characterise Migraine Risk Loci

Gerring¹

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Migraine is a frequent, debilitating and painful headache disorder that normally affects people during their most productive years of life (25% of females and 8% of males).Genome-wide association studies have identified 44 independent single nucleotide polymorphisms associated with migraine, however the causal genes and pathogenic mechanisms underlying the disorder remain unknown. Therefore, we performed a multi-staged integrated study of gene expression and DNA methylation in a large sample of migraine cases and non-migraine controls from the Brisbane Systems Genetics Study. We identified several gene expression networks and differentially methylated regions associated with migraine, which were subsequently characterised using robust statistical and pathway-based approaches. Integration of existing genomewide association data with gene expression and methylation data prioritised migraine susceptibility genes for further functional characterisation. This study suggests the use of multiple molecular data to study existing migraine loci has the potential to provide a substantial contribution to understanding the underlying genetic architecture and biological mechanisms of migraine, and may help in the development of diagnostic tests and new targets for drug therapy.3

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Casein Kinase Iδ Mutations in Familial Migraine and Advanced Sleep Phase

Cited by 183 publications

References 48 publications

The intricate dance of post-translational modifications in the rhythm of life

The intricate dance of post-translational modifications in the rhythm of life

A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait

Integrating Genome-Wide Association and Blood Genomic Profiling Data to Characterise Migraine Risk Loci

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