Human CRY1 variants associate with attention deficit/hyperactivity disorder

Onat, Onur Emre; Kars, Meltem Ece; Gül, Şeref; Bilgüvar, Kaya; Wu, Yiming; Özhan, Ayşe; Aydın, Cihan; Basak, A. Nazli; Trusso, Maria Allegra; Goracci, Arianna; Fallerini, Chiara; Renieri, Alessandra; Casanova, Jean‐Laurent; Itan, Yuval; Atbaşoğlu, Cem; Saka, Meram Can; Kavaklı, İbrahim Halil; Özçelık, Tayfun

doi:10.1172/jci135500

Cited by 38 publications

(32 citation statements)

References 61 publications

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“…Moreover, mutational analysis of CRYs indicated that residues around the secondary pocket of CRY1 and CRY2 are critical for the CLOCK binding and their repression activity (31). In fact, a human gain-of-function CRY1 variant (exon 11 skipping mutation in C-tail of CRY1) found in people suffering from familial delayed sleep phase disorder and attention deficit/hyperactivity disorder exhibits high affinity to BMAL1/CLOCK (32,33).…”

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confidence: 99%

The Arg-293 of Cryptochrome1 is responsible for the allosteric regulation of CLOCK-CRY1 binding in circadian rhythm

Gül

Aydın

Ozcan

et al. 2020

Journal of Biological Chemistry

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Mammalian circadian clocks are driven by transcription/translation feedback loops composed of positive transcriptional activators (BMAL1 and CLOCK) and negative repressors (CRYPTOCHROMEs (CRYs) and PERIODs (PERs)). CRYs, in complex with PERs, bind to the BMAL1/CLOCK complex and repress E-box driven transcription of clock associated genes. There are two individual CRYs, with CRY1 exhibiting higher affinity to the BMAL1/CLOCK complex than CRY2. It is known that this differential binding is regulated by a dynamic serine-rich loop adjacent to the secondary pocket of both CRYs, but the underlying features controlling loop dynamics are not known. Here we report that allosteric regulation of the serine-rich loop is mediated by Arg293 of CRY1, identified as a rare CRY1 SNPs in the Ensembl and 1000 Genomes databases. The p.Arg293His CRY1 variant caused a shortened circadian period in a Cry1-/-Cry2-/-double knockout mouse embryonic fibroblast cell line. Moreover, the variant displayed reduced repressor activity on BMAL1/CLOCK driven transcription, which is explained by reduced affinity to BMAL1/CLOCK in the absence of PER2 compared to wild type CRY1. Molecular dynamics simulations revealed that the p.Arg293His CRY1 variant altered a communication pathway between Arg293 and the serine loop, by reducing its dynamicity. Collectively, this study provides direct evidence that allosterism in CRY1 is critical for the regulation of circadian rhythm.

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confidence: 99%

The Arg-293 of Cryptochrome1 is responsible for the allosteric regulation of CLOCK-CRY1 binding in circadian rhythm

Gül

Aydın

Ozcan

et al. 2020

Journal of Biological Chemistry

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“…For example, CRY1 variants have been associated with depression and mood disorders 8 , 61 , 62 , elevated blood pressure and hypertension 62 . Additionally, a CRY1 variant is linked with familial delayed sleep phase disorder and attention deficit/hyperactivity disorder 18 , 63 . We, therefore, selected mammalian CRY1 as a target for in silico screening to find molecules that regulate the period of the circadian rhythm.…”

Section: Resultsmentioning

confidence: 99%

Structure-based design and classifications of small molecules regulating the circadian rhythm period

Gül

Rahim

Isin³

et al. 2021

Sci Rep

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Circadian rhythm is an important mechanism that controls behavior and biochemical events based on 24 h rhythmicity. Ample evidence indicates disturbance of this mechanism is associated with different diseases such as cancer, mood disorders, and familial delayed phase sleep disorder. Therefore, drug discovery studies have been initiated using high throughput screening. Recently the crystal structures of core clock proteins (CLOCK/BMAL1, Cryptochromes (CRY), Periods), responsible for generating circadian rhythm, have been solved. Availability of structures makes amenable core clock proteins to design molecules regulating their activity by using in silico approaches. In addition to that, the implementation of classification features of molecules based on their toxicity and activity will improve the accuracy of the drug discovery process. Here, we identified 171 molecules that target functional domains of a core clock protein, CRY1, using structure-based drug design methods. We experimentally determined that 115 molecules were nontoxic, and 21 molecules significantly lengthened the period of circadian rhythm in U2OS cells. We then performed a machine learning study to classify these molecules for identifying features that make them toxic and lengthen the circadian period. Decision tree classifiers (DTC) identified 13 molecular descriptors, which predict the toxicity of molecules with a mean accuracy of 79.53% using tenfold cross-validation. Gradient boosting classifiers (XGBC) identified 10 molecular descriptors that predict and increase in the circadian period length with a mean accuracy of 86.56% with tenfold cross-validation. Our results suggested that these features can be used in QSAR studies to design novel nontoxic molecules that exhibit period lengthening activity.

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“…Until now, studies of the CRY1 gene polymorphism have been conducted in humans. Mutations located in this gene were associated with major depressive disorder (MDD), insomnia, and anxiety [ 47 , 48 ]. Our results are the first in this regard in a non-human species.…”

Section: Discussionmentioning

confidence: 99%

CRY1 Gene Polymorphism and Racing Performance of Homing Pigeons

Dybus

Kulig

et al. 2021

Animals

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Cryptochromes (CRY) are the family of proteins proposed as the putative magnetoreceptor molecules. In birds, among others in pigeons, CRY1 is widely expressed in a retina. Homing pigeons are known for their navigational abilities, and pigeon racing is a popular sport. So, the purpose of this study was to analyze the variability of the nucleotide sequence of the homing pigeon CRY1 gene, spanning the region coding the two amino acids W320 and W374 of Trp-triad, and estimate the relationship between genotypes and the racing performance. Investigations were carried out on 129 pigeons. Analysis of sequencing results indicated the AG to TT change within the seventh intron of CRY1 gene. Genotypes were determined by the forced PCR-RFLP method. The influence of detected polymorphism on the results of racing pigeons in 100–400 km flights was shown. The AG/TT individuals achieved significantly higher (p ≤ 0.05) mean values of ace points (AP) than the AG/AG ones. Regarding the detected nucleotide change localization, the polymorphism may be involved in CRY1 gene expression modulation. The AG to TT change in CRY1 gene may be considered as a potential genetic marker of racing performance in homing pigeons.

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Human CRY1 variants associate with attention deficit/hyperactivity disorder

Cited by 38 publications

References 61 publications

The Arg-293 of Cryptochrome1 is responsible for the allosteric regulation of CLOCK-CRY1 binding in circadian rhythm

The Arg-293 of Cryptochrome1 is responsible for the allosteric regulation of CLOCK-CRY1 binding in circadian rhythm

Structure-based design and classifications of small molecules regulating the circadian rhythm period

CRY1 Gene Polymorphism and Racing Performance of Homing Pigeons

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