CRY1

Summary

CRY1 (cryptochrome circadian regulator 1, HGNC:2384) is a protein-coding gene on chromosome 12q23.3, encoding Cryptochrome-1 (Q16526). Transcriptional repressor which forms a core component of the circadian clock.

This gene encodes a flavin adenine dinucleotide-binding protein that is a key component of the circadian core oscillator complex, which regulates the circadian clock. This gene is upregulated by CLOCK/ARNTL heterodimers but then represses this upregulation in a feedback loop using PER/CRY heterodimers to interact with CLOCK/ARNTL. Polymorphisms in this gene have been associated with altered sleep patterns. The encoded protein is widely conserved across plants and animals. Loss of the related gene in mouse results in a shortened circadian cycle in complete darkness.

Source: NCBI Gene 1407 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 81 total
• Phenotypes (HPO): 2
• Druggable target: yes
• MANE Select transcript: NM_004075

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2384
Approved symbol	CRY1
Name	cryptochrome circadian regulator 1
Location	12q23.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000008405
Ensembl biotype	protein_coding
OMIM	601933
Entrez	1407

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000008527, ENST00000546722, ENST00000549356, ENST00000550633, ENST00000552790, ENST00000864076, ENST00000864077, ENST00000938851, ENST00000938852, ENST00000947484

RefSeq mRNA: 14 — MANE Select: NM_004075 NM_001413458, NM_001413459, NM_001413460, NM_001413461, NM_001413462, NM_001413463, NM_001413464, NM_001413465, NM_001413466, NM_001413467, NM_001413468, NM_001413469, NM_001413470, NM_004075

CCDS: CCDS9112

Canonical transcript exons

ENST00000008527 — 13 exons

Exon	Start	End
ENSE00000497379	106997294	106997386
ENSE00000754534	106992965	106993036
ENSE00001165053	107092804	107093549
ENSE00002398374	106991364	106992001
ENSE00002408243	106992787	106992890
ENSE00003502178	106999551	106999862
ENSE00003502783	107001764	107001948
ENSE00003514738	106999942	107000082
ENSE00003546264	107001280	107001368
ENSE00003590600	107022084	107022192
ENSE00003597160	106997488	106997690
ENSE00003670410	107005106	107005248
ENSE00003681751	106997915	106998066

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 98.96.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.3583 / max 182.3649, expressed in 1776 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
133090	11.3664	1754
133091	2.6318	1301
133089	2.0045	935
133094	0.7003	454
133093	0.2210	86
133087	0.1335	21
133092	0.1099	38
206880	0.0969	21
133088	0.0941	26

Top tissues by expression

297 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	98.96	gold quality
secondary oocyte	CL:0000655	98.89	gold quality
cartilage tissue	UBERON:0002418	96.14	gold quality
visceral pleura	UBERON:0002401	95.48	gold quality
tibia	UBERON:0000979	95.11	gold quality
germinal epithelium of ovary	UBERON:0001304	95.09	gold quality
adult organism	UBERON:0007023	95.05	gold quality
parietal pleura	UBERON:0002400	95.01	gold quality
sperm	CL:0000019	94.83	gold quality
cauda epididymis	UBERON:0004360	94.83	gold quality
bronchial epithelial cell	CL:0002328	94.67	gold quality
amniotic fluid	UBERON:0000173	94.41	gold quality
choroid plexus epithelium	UBERON:0003911	94.18	gold quality
pleura	UBERON:0000977	94.02	gold quality
jejunal mucosa	UBERON:0000399	93.83	gold quality
heart right ventricle	UBERON:0002080	93.56	gold quality
mucosa of sigmoid colon	UBERON:0004993	93.34	gold quality
male germ cell	CL:0000015	93.01	gold quality
cerebellar vermis	UBERON:0004720	92.79	gold quality
caput epididymis	UBERON:0004358	92.60	gold quality
blood vessel layer	UBERON:0004797	92.15	gold quality
saphenous vein	UBERON:0007318	92.11	gold quality
synovial joint	UBERON:0002217	91.99	gold quality
jejunum	UBERON:0002115	91.87	gold quality
endothelial cell	CL:0000115	91.77	gold quality
mucosa of paranasal sinus	UBERON:0005030	91.57	gold quality
colonic mucosa	UBERON:0000317	91.02	gold quality
epithelium of nasopharynx	UBERON:0001951	90.85	gold quality
epithelial cell of pancreas	CL:0000083	90.56	gold quality
oral cavity	UBERON:0000167	90.40	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
SERPINE1

Upstream regulators (CollecTRI, top): BHLHE40, BMAL1, CLOCK, FOS, MTA1, MYC, NPAS2, PITX2, RAI1, TTF1

miRNA regulators (miRDB)

75 targeting CRY1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-454-3P	99.91	74.01	1925

Literature-anchored findings (GeneRIF, showing 40)

• Linkage disequilibrium analyses using single SNPs and haplotypes showed no association to bipolar disease. (PMID:15722957)
• the CLOCK(NPAS2)/BMAL1 complex is post-translationally regulated by cry1 and cry2 (PMID:16628007)
• Cry1 may be a candidate gene of schizophrenia. The proposition may have new clues on the development of genetic study on complex diseases (PMID:17376600)
• The regulators of clock-controlled transcription PER2, CRY1 and CRY2 differ in their capacity to interact with each single component of the BMAL1-CLOCK heterodimer and, in the case of BMAL1, also in their interaction sites. (PMID:18430226)
• Cryptochrome-1 was a valuable predictor of disease progression in early-stage chronic lymphocytic leukemia (PMID:19181792)
• differential expression and prognostic significance of the circadian genes CRY1 and PER2 in chronic lymphocytic leukemia (PMID:19500131)
• There was no circadian rhythm of bmal1(brain and muscle ARNT-like 1) and cry1(cryptochrome 1) in PBMC of preterm neonates (PMID:20222832)
• Five SNPs were validated as being significantly associated with prostate cancer mortality, one each in the LEPR, CRY1, RNASEL, IL4, and ARVCF genes. (PMID:21846818)
• Clock genes expression is sex dependent in human adipose tissue from morbidly obese subjects and correlates to a decreased in metabolic syndrome-related traits. (PMID:22081238)
• Human cryptochrome-1 confers light independent biological activity in transgenic Drosophila correlated with flavin radical stability. (PMID:22427812)
• The methylation pattern of the CRY1 promoter proved to have high prognostic impact in CLL where aberrant promoter methylation predicted a favourable outcome. (PMID:22470559)
• Genetic variants of CRY1 associate with depressive disorder. (PMID:22538398)
• USP2a potentially mediates circadian disruption by suppressing the CRY1 degradation during inflammation. (PMID:22669941)
• the CRY1-PHR domain(313-426), not the divergent C-terminal domain, is critical for clock function. (PMID:22692217)
• type II protein arginine methyltransferase 5 has a role in the regulation of Circadian Per1 and CRY1 genes (PMID:23133559)
• Loss of Cry1 expression is associated with skin tumors. (PMID:23242607)
• Reduced cry1 expression is associated with glioma. (PMID:23317246)
• Studies indicate that in the cytoplasm, PER3 protein heterodimerizes with PER1, PER2, CRY1, and CRY2 proteins and enters into the nucleus, resulting in repression of CLOCK-BMAL1-mediated transcription. (PMID:23546644)
• Data suggest that clock genes Per1, Cry1, Clock, and Bmal1 and their protein products may be directly involved in the daytime-dependent regulation and adaptation of hormone synthesis. (PMID:23584858)
• Cry1 likely plays important roles in colorectal cancer development and progression. (PMID:23626715)
• data suggest a new role for the C-terminal tail of CRY1 in which phosphorylation rhythmically regulates CRY1 stability and contributes to the proper circadian period length (PMID:24158435)
• Casein kinase 1 primarily regulates the accumulating phase of the PER-CRY repressive complex by controlling the nuclear import rate. (PMID:24449901)
• Study reveals an interaction between a CRY1 variant and carbohydrate intake for glucose metabolism. (PMID:24548145)
• findings show the polymorphisms of Cry1 rs2287161 and Tef rs738499 are associated to major depressive disorder in the Chinese population (PMID:24581835)
• SNPs in CRY1 were significantly associated with overall survival in Chinese hepatocellular carcinoma patients. (PMID:25344870)
• CRY1 and CRY2 variants showed nominal association with the metabolic syndrome components, hypertension and triglyceride levels. (PMID:25391456)
• these observations suggest a biologically plausible season-dependent association between SNPs at CRY1, CRY2 and MTNR1B and glucose homeostasis. (PMID:25707907)
• In men undergoing acute total sleep deprivation, there was increased methylation in the promoter of CRY1 in adipose tissue compared with controls. Also decreased gene expression in skeletal muscle. (PMID:26168277)
• Overexpression of CRY1 protects against the development of atherosclerosis via the TLR/NFkappaB pathway (PMID:26218278)
• possible circadian rhythm in full-term placental expression (PMID:26247999)
• Collectively, these data show that KPNB1 is required for timely nuclear import of PER/CRY in the negative feedback regulation of the circadian clock. (PMID:26319354)
• Altered CRY1 and CRY2 expression patterns and the interplay with the genetic landscape in colon cancer cells may underlie phenotypic divergence. (PMID:26768731)
• Our findings suggest that CLOCK and CRY1 polymorphisms might be involved in individual susceptibility to abdominal obesity in Chinese Han population. (PMID:26923944)
• Given the distinct characteristics of the C-terminal tails of the CRY1 and CRY2 proteins, our study addresses a long-standing hypothesis that the ratio of these two CRY molecules affects the clock period. (PMID:26966073)
• The present study identified USP7 and TDP-43 as the regulators of CRY1 and CRY2, underscoring the significance of the stability control process of CRY proteins for period determination in the mammalian circadian clockwork. (PMID:27123980)
• CRY1 SNP rs714359 showed nominally significant association with the problematicity of seasonal variations (problematic vs. no variation) of mood disorder. The set-based analysis did not support these associations. However, the CRY1 haplotype TAG including rs714359 showed nominally significant association with the problematicity of seasonal variations in mood disorder. (PMID:27267441)
• CRY1 variants were not associated with major depressive disorder. (PMID:27721187)
• Knockout-rescue embryonic stem cell-derived mouse reveals that CRY1 determines circadian period through both its degradation-dependent and -independent pathways. (PMID:28017587)
• Study confirms the prognostic role of CRY1 in chronic lymphocytic leukemia, as its aberrant methylation and expression is associated with high risk of treatment initiation and survival. (PMID:28572861)
• CRY1/2 serve as corepressors for many NRs. (PMID:28751364)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	cry1b	ENSDARG00000011583
danio_rerio	cry1a	ENSDARG00000045768
mus_musculus	Cry1	ENSMUSG00000020038
rattus_norvegicus	Cry1	ENSRNOG00000006622

Paralogs (1): CRY2 (ENSG00000121671)

Protein

Protein identifiers

Cryptochrome-1 — Q16526 (reviewed: Q16526)

All UniProt accessions (3): Q16526, A2I2P0, H0YHT0

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional repressor which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots ‘circa’ (about) and ‘diem’ (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for ’timegivers’). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5’-CACGTG-3’) within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress BMAL1 transcription, respectively. CRY1 and CRY2 have redundant functions but also differential and selective contributions at least in defining the pace of the SCN circadian clock and its circadian transcriptional outputs. More potent transcriptional repressor in cerebellum and liver than CRY2, though more effective in lengthening the period of the SCN oscillator. On its side, CRY2 seems to play a critical role in tuning SCN circadian period by opposing the action of CRY1. With CRY2, is dispensable for circadian rhythm generation but necessary for the development of intercellular networks for rhythm synchrony. Capable of translocating circadian clock core proteins such as PER proteins to the nucleus. Interacts with CLOCK-BMAL1 independently of PER proteins and is found at CLOCK-BMAL1-bound sites, suggesting that CRY may act as a molecular gatekeeper to maintain CLOCK-BMAL1 in a poised and repressed state until the proper time for transcriptional activation. Represses the CLOCK-BMAL1 induced transcription of BHLHE40/DEC1. Represses the CLOCK-BMAL1 induced transcription of ATF4, MTA1, KLF10 and NAMPT. May repress circadian target genes expression in collaboration with HDAC1 and HDAC2 through histone deacetylation. Mediates the clock-control activation of ATR and modulates ATR-mediated DNA damage checkpoint. In liver, mediates circadian regulation of cAMP signaling and gluconeogenesis by binding to membrane-coupled G proteins and blocking glucagon-mediated increases in intracellular cAMP concentrations and CREB1 phosphorylation. Inhibits hepatic gluconeogenesis by decreasing nuclear FOXO1 levels that down-regulates gluconeogenic gene expression. Besides its role in the maintenance of the circadian clock, is also involved in the regulation of other processes. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by binding to glucocorticoid response elements (GREs). Plays a key role in glucose and lipid metabolism modulation, in part, through the transcriptional regulation of genes involved in these pathways, such as LEP or ACSL4. Represses PPARD and its target genes in the skeletal muscle and limits exercise capacity. Plays an essential role in the generation of circadian rhythms in the retina. Represses the transcriptional activity of NR1I2.

Subunit / interactions. Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E, TIMELESS, and the PER proteins. Interacts directly with TIMELESS. Interacts directly with PER1 and PER3. Interacts directly with PER2; interaction with PER2 inhibits its ubiquitination and vice versa. Interacts with FBXL21. Interacts with FBXL3. Interacts with PPP5C (via TPR repeats). Interacts with CLOCK-BMAL1 independently of PER2 and DNA. Interacts with HDAC1, HDAC2 and SIN3B. Interacts with nuclear receptors AR, NR1D1, NR3C1/GR, RORA and RORC; the interaction with at least NR3C1/GR is ligand dependent. Interacts with PRKDC. Interacts with the G protein subunit alpha GNAS; the interaction may block GPCR-mediated regulation of cAMP concentrations. Interacts with PRMT5. Interacts with EZH2. Interacts with MYBBP1A, DOCK7, HNRNPU, RPL7A, RPL8 and RPS3. Interacts with MAP1LC3B. Interacts with CLOCK. Interacts with BMAL1. Interacts weakly with HDAC3; this interaction is enhanced in the presence of FBXL3. Interacts with TRIM28, KCTD5 and DDB1. Interacts with FOXO1. Interacts with DTL and DDB1-CUL4A complex. Interacts with HNF4A. Interacts with PSMD2 in a KDM8-dependent manner. Interacts with KDM8 in a FBXL3-dependent manner. Interacts with PPARG in a ligand-dependent manner. Interacts with PPARD (via domain NR LBD) and NR1I2 (via domain NR LBD) in a ligand-dependent manner. Interacts with PPARA, NR1I3 and VDR.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Phosphorylation on Ser-247 by MAPK is important for the inhibition of CLOCK-BMAL1-mediated transcriptional activity. Phosphorylation by CSNK1E requires interaction with PER1 or PER2. Phosphorylation at Ser-71 and Ser-280 by AMPK decreases protein stability. Phosphorylation at Ser-568 exhibits a robust circadian rhythm with a peak at CT8, increases protein stability, prevents SCF(FBXL3)-mediated degradation and is antagonized by interaction with PRKDC. Ubiquitinated by the SCF(FBXL3) and SCF(FBXL21) complexes, regulating the balance between degradation and stabilization. The SCF(FBXL3) complex is mainly nuclear and mediates ubiquitination and subsequent degradation of CRY1. In contrast, cytoplasmic SCF(FBXL21) complex-mediated ubiquitination leads to stabilize CRY1 and counteract the activity of the SCF(FBXL3) complex. The SCF(FBXL3) and SCF(FBXL21) complexes probably mediate ubiquitination at different Lys residues. Ubiquitination at Lys-11 and Lys-107 are specifically ubiquitinated by the SCF(FBXL21) complex but not by the SCF(FBXL3) complex. Ubiquitination may be inhibited by PER2. Deubiquitinated by USP7. Undergoes autophagy-mediated degradation in the liver in a time-dependent manner. Autophagic degradation of CRY1 (an inhibitor of gluconeogenesis) occurs during periods of reduced feeding allowing induction of gluconeogenesis and maintenance of blood glucose levels.

Disease relevance. Delayed sleep phase syndrome (DSPS) [MIM:614163] A circadian rhythm sleep disorder characterized by sleep-onset insomnia and difficulty in awakening at the desired time. Patients with DSPS have chronic difficulty in adjusting their sleep-onset and wake-up times to occupational, school, and social activities. Disease susceptibility is associated with variants affecting the gene represented in this entry. An adenine-to-cytosine transversion within the 5’splice site following exon 11 has been found in multiple members of a DSPD family and segregates with the disorder with autosomal dominant inheritance pattern. This variant is predicted to cause exon 11 skipping and in-frame deletion of 24 residues in the C-terminal region of CRY1. Functional studies show that the mutated protein acts as a more potent transcriptional repressor than wild-type, causes reduced expression of key transcriptional targets and lengthens the period of circadian molecular rhythms.

Activity regulation. KL001 (N-[3-(9H-carbazol-9-yl)-2-hydroxypropyl]-N-(2-furanylmethyl)-methanesulfonamide) binds to CRY1 and stabilizes it by inhibiting FBXL3- and ubiquitin-dependent degradation of CRY1 resulting in lengthening of the circadian periods.

Cofactor. Binds 1 FAD per subunit. Only a minority of the protein molecules contain bound FAD. Contrary to the situation in photolyases, the FAD is bound in a shallow, surface-exposed pocket. Binds 1 5,10-methenyltetrahydrofolate (MTHF) non-covalently per subunit.

Domain organisation. The LIR motifs (LC3-interacting region) 3 and 5 are required for its interaction with MAP1LC3B and for its autophagy-mediated degradation.

Induction. Expression is regulated by light and circadian rhythms and osicllates diurnally. Peak expression in the suprachiasma nucleus (SCN) and eye at the day/night transition (CT12). Levels decrease with BMAL1-CLOCK inhibition as part of the autoregulatory feedback loop.

Similarity. Belongs to the DNA photolyase class-1 family.

RefSeq proteins (14): NP_001400387, NP_001400388, NP_001400389, NP_001400390, NP_001400391, NP_001400392, NP_001400393, NP_001400394, NP_001400395, NP_001400396, NP_001400397, NP_001400398, NP_001400399, NP_004066* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002081	Cryptochrome/DNA_photolyase_1	Family
IPR005101	Cryptochr/Photolyase_FAD-bd	Domain
IPR006050	DNA_photolyase_N	Domain
IPR014729	Rossmann-like_a/b/a_fold	Homologous_superfamily
IPR036134	Crypto/Photolyase_FAD-like_sf	Homologous_superfamily
IPR036155	Crypto/Photolyase_N_sf	Homologous_superfamily

Pfam: PF00875, PF03441

UniProt features (34 total): short sequence motif 13, cross-link 6, binding site 4, modified residue 4, region of interest 3, mutagenesis site 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16526-F1	85.32	0.75

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (4): 252; 289; 355; 387–389

Post-translational modifications (10): 71, 247, 280, 568, 11, 107, 159, 329, 485, 565

Mutagenesis-validated functional residues (2):

Position	Phenotype
387	loss of binding to kl001.
393	loss of binding to kl001.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-9931510	Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes
R-HSA-9931521	The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex
R-HSA-9931530	Phosphorylation and nuclear translocation of the CRY:PER:kinase complex
R-HSA-9932298	Degradation of CRY and PER proteins
R-HSA-9931512	Phosphorylation of CLOCK, acetylation of BMAL1 (ARNTL) at target gene promoters

MSigDB gene sets: 377 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, GSE45365_NK_CELL_VS_CD8_TCELL_UP, GOBP_CIRCADIAN_RHYTHM, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_CELL_CYCLE_CHECKPOINT, KANG_FLUOROURACIL_RESISTANCE_UP, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_PHOTOPERIODISM, BROWNE_HCMV_INFECTION_8HR_UP, SP3_Q3, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_HORMONE_TRANSPORT

GO Biological Process (26): negative regulation of transcription by RNA polymerase II (GO:0000122), gluconeogenesis (GO:0006094), circadian rhythm (GO:0007623), response to light stimulus (GO:0009416), blue light signaling pathway (GO:0009785), response to activity (GO:0014823), lipid storage (GO:0019915), negative regulation of protein ubiquitination (GO:0031397), positive regulation of protein ubiquitination (GO:0031398), response to insulin (GO:0032868), circadian regulation of gene expression (GO:0032922), response to glucagon (GO:0033762), glucose homeostasis (GO:0042593), regulation of circadian rhythm (GO:0042752), negative regulation of circadian rhythm (GO:0042754), signal transduction in response to DNA damage (GO:0042770), entrainment of circadian clock by photoperiod (GO:0043153), negative regulation of gluconeogenesis (GO:0045721), positive regulation of gluconeogenesis (GO:0045722), negative regulation of G protein-coupled receptor signaling pathway (GO:0045744), negative regulation of DNA-templated transcription (GO:0045892), regulation of DNA damage checkpoint (GO:2000001), negative regulation of nuclear receptor-mediated glucocorticoid signaling pathway (GO:2000323), negative regulation of glucocorticoid secretion (GO:2000850), regulation of gluconeogenesis (GO:0006111), rhythmic process (GO:0048511)

GO Molecular Function (15): DNA binding (GO:0003677), double-stranded DNA binding (GO:0003690), blue light photoreceptor activity (GO:0009882), nuclear receptor binding (GO:0016922), protein kinase binding (GO:0019901), phosphatase binding (GO:0019902), histone deacetylase binding (GO:0042826), E-box binding (GO:0070888), FAD binding (GO:0071949), nucleotide binding (GO:0000166), protein binding (GO:0005515), photoreceptor activity (GO:0009881), lyase activity (GO:0016829), kinase binding (GO:0019900), DNA-binding transcription factor binding (GO:0140297)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Circadian clock	5

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
circadian rhythm	3
enzyme binding	3
protein ubiquitination	2
regulation of protein ubiquitination	2
response to peptide hormone	2
gluconeogenesis	2
regulation of gluconeogenesis	2
intracellular membrane-bounded organelle	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
glucose metabolic process	1
hexose biosynthetic process	1
rhythmic process	1
response to radiation	1
intracellular receptor signaling pathway	1
cellular response to blue light	1
response to stimulus	1
nutrient storage	1
negative regulation of protein modification by small protein conjugation or removal	1
positive regulation of protein modification by small protein conjugation or removal	1
regulation of gene expression	1
carbohydrate homeostasis	1
regulation of biological process	1
regulation of circadian rhythm	1
negative regulation of biological process	1
DNA damage response	1
intracellular signal transduction	1
photoperiodism	1
entrainment of circadian clock	1
negative regulation of biosynthetic process	1
negative regulation of carbohydrate metabolic process	1
negative regulation of small molecule metabolic process	1
positive regulation of biosynthetic process	1
positive regulation of glucose metabolic process	1
G protein-coupled receptor signaling pathway	1
regulation of G protein-coupled receptor signaling pathway	1
negative regulation of signal transduction	1
nucleic acid binding	1
DNA binding	1

Protein interactions and networks

STRING

2335 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CRY1	PER2	O15055	999
CRY1	BMAL1	O00327	998
CRY1	CLOCK	O15516	996
CRY1	TIMELESS	Q9UNS1	996
CRY1	FBXL3	Q9UKT7	995
CRY1	PER3	P56645	991
CRY1	NR1D1	P20393	977
CRY1	NPAS2	Q99743	976
CRY1	BHLHE41	Q9C0J9	958
CRY1	BHLHE40	O14503	957
CRY1	NR1D2	Q14995	949
CRY1	NFIL3	Q16649	941
CRY1	A0A087WZY1	A0A087WZY1	940
CRY1	CSNK1E	P49674	938
CRY1	PRH1	P02810	936

IntAct

81 interactions, top by confidence:

A	B	Type	Score
Bmal1	Clock	psi-mi:“MI:0914”(association)	0.970
CSNK1E	MCC	psi-mi:“MI:0914”(association)	0.890
BMAL1	CLOCK	psi-mi:“MI:0914”(association)	0.880
CLOCK	BMAL1	psi-mi:“MI:0914”(association)	0.880
CSNK1E	PER2	psi-mi:“MI:0914”(association)	0.850
CSNK1E	PER1	psi-mi:“MI:0914”(association)	0.840
CSNK1D	PER2	psi-mi:“MI:0914”(association)	0.810
QPRT	PIK3C2A	psi-mi:“MI:0914”(association)	0.640
CRY1	CUL1	psi-mi:“MI:0914”(association)	0.640
FBXL3	CRY1	psi-mi:“MI:0914”(association)	0.640
CRY1	SKP1	psi-mi:“MI:0914”(association)	0.640
SKP1	MYCBP2	psi-mi:“MI:0914”(association)	0.640
PER1	CRY1	psi-mi:“MI:0915”(physical association)	0.560
Cry1	PER1	psi-mi:“MI:0915”(physical association)	0.560
BAIAP2	WASL	psi-mi:“MI:0914”(association)	0.550
PLSCR1	CRY1	psi-mi:“MI:0915”(physical association)	0.550
BMAL2	CLOCK	psi-mi:“MI:0914”(association)	0.550
CRY1	PLSCR1	psi-mi:“MI:0915”(physical association)	0.550
CSNK1E	POTEF	psi-mi:“MI:0914”(association)	0.530
TEKT4	CLOCK	psi-mi:“MI:0914”(association)	0.530
FBXL3	RFX1	psi-mi:“MI:0914”(association)	0.530
CRY1	CLOCK	psi-mi:“MI:0914”(association)	0.530

BioGRID (228): CRY1 (Two-hybrid), CRY1 (Two-hybrid), CSNK2B (Two-hybrid), DEC1 (Two-hybrid), BHLHE41 (Two-hybrid), NPAS2 (Two-hybrid), PER2 (Two-hybrid), PPP2R5E (Two-hybrid), CSNK1E (Two-hybrid), PER1 (Two-hybrid), PPP2R1B (Two-hybrid), PPP2R5D (Two-hybrid), NR1D2 (Two-hybrid), ARNTL (Affinity Capture-Luminescence), CRY1 (Affinity Capture-MS)

ESM2 similar proteins: A2ARP1, A2RSY6, A4QNR3, A5D7S3, A6H8I2, A7Z050, B0WRR9, O48652, O77059, P0C644, P34205, P41229, P41230, P97784, Q01433, Q02356, Q0E2Y1, Q16526, Q17DK5, Q17QN2, Q293P8, Q2KI13, Q32Q86, Q38JA7, Q43125, Q49AN0, Q5IZC5, Q5RDF1, Q6P6R7, Q6PFW1, Q6ZZY0, Q70AD6, Q7PYI7, Q7T2D0, Q8BHD8, Q8QG60, Q8QG61, Q8R0P8, Q8VCZ6, Q8VEG4

Diamond homologs: A9CJC9, B0WRR9, O48652, O77059, P00914, P05327, P12768, P25078, P57386, P61496, P61497, P77967, P97784, Q04449, Q0E2Y1, Q16526, Q17DK5, Q293P8, Q32Q86, Q38JU2, Q3IPX9, Q43125, Q49AN0, Q55081, Q5IZC5, Q651U1, Q6ZZY0, Q70AD6, Q7NMD1, Q7PYI7, Q7SI68, Q84KJ5, Q8QG60, Q8QG61, Q8WP19, Q923I8, Q9KNA8, Q9R194, P40115, Q75WS4

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
PRKAA1	down-regulates	CRY1	phosphorylation
AMPK	down-regulates	CRY1	phosphorylation
BMAL1/NPAS2	“up-regulates quantity by expression”	CRY1	“transcriptional regulation”
CRY1	“down-regulates activity”	BMAL1/NPAS2	binding
CRY1	“down-regulates activity”	CLOCK/BMAL1	binding
AMPK	“down-regulates quantity by destabilization”	CRY1	phosphorylation
RAI1	“up-regulates quantity by expression”	CRY1	“transcriptional regulation”
ARNTL	“up-regulates quantity by expression”	CRY1	“transcriptional regulation”
CLOCK	“up-regulates quantity by expression”	CRY1	“transcriptional regulation”
CLOCK/BMAL1	“up-regulates quantity by expression”	CRY1	“transcriptional regulation”
TIMELESS	“up-regulates activity”	CRY1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 75 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex	7	102.0×	8e-11
Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes	6	58.3×	8e-08
R-HSA-400253	7	49.4×	1e-08
BMAL1:CLOCK,NPAS2 activates circadian expression	5	43.2×	5e-06
Degradation of CRY and PER proteins	6	26.9×	5e-06
Regulation of PLK1 Activity at G2/M Transition	5	12.9×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
entrainment of circadian clock by photoperiod	5	58.1×	2e-06
circadian regulation of gene expression	11	40.9×	1e-12
regulation of circadian rhythm	9	37.0×	6e-10
circadian rhythm	7	27.1×	9e-07
proteasome-mediated ubiquitin-dependent protein catabolic process	8	6.6×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

81 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	63
Likely benign	4
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

2042 predictions. Top by Δscore:

Variant	Effect	Δscore
12:106997292:A:AC	donor_gain	1.0000
12:106997292:ACTT:A	donor_gain	1.0000
12:106997293:C:CA	donor_gain	1.0000
12:106997293:CTT:C	donor_gain	1.0000
12:106997293:CTTC:C	donor_gain	1.0000
12:106997295:T:TA	donor_gain	1.0000
12:106997387:C:CA	acceptor_loss	1.0000
12:106997387:C:CC	acceptor_gain	1.0000
12:106997484:ATAC:A	donor_loss	1.0000
12:106997485:TA:T	donor_loss	1.0000
12:106997487:C:CG	donor_loss	1.0000
12:106997490:AGT:A	donor_gain	1.0000
12:106997686:AACGC:A	acceptor_gain	1.0000
12:106997687:ACGC:A	acceptor_gain	1.0000
12:106997688:CGC:C	acceptor_gain	1.0000
12:106997688:CGCC:C	acceptor_gain	1.0000
12:106997688:CGCCT:C	acceptor_loss	1.0000
12:106997689:GC:G	acceptor_gain	1.0000
12:106997689:GCCTT:G	acceptor_loss	1.0000
12:106997690:CCTT:C	acceptor_gain	1.0000
12:106997691:C:CC	acceptor_gain	1.0000
12:106997691:C:T	acceptor_gain	1.0000
12:106997692:T:C	acceptor_gain	1.0000
12:106997693:T:C	acceptor_gain	1.0000
12:106999546:CTTA:C	donor_loss	1.0000
12:106999547:TTAC:T	donor_loss	1.0000
12:106999548:TACCT:T	donor_loss	1.0000
12:106999549:A:AC	donor_gain	1.0000
12:106999549:ACC:A	donor_loss	1.0000
12:106999550:C:CC	donor_gain	1.0000

AlphaMissense

3846 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:106997927:C:A	G426V	1.000
12:106997927:C:T	G426E	1.000
12:106997928:C:G	G426R	1.000
12:106997928:C:T	G426R	1.000
12:106997948:C:T	G419D	1.000
12:106997950:A:C	F418L	1.000
12:106997950:A:T	F418L	1.000
12:106997952:A:G	F418L	1.000
12:106997960:G:T	P415H	1.000
12:106997974:A:C	F410L	1.000
12:106997974:A:T	F410L	1.000
12:106997976:A:G	F410L	1.000
12:106997977:A:C	F409L	1.000
12:106997977:A:T	F409L	1.000
12:106997979:A:G	F409L	1.000
12:106997986:A:C	F406L	1.000
12:106997986:A:T	F406L	1.000
12:106997988:A:G	F406L	1.000
12:106997995:A:C	S403R	1.000
12:106997995:A:T	S403R	1.000
12:106997997:T:G	S403R	1.000
12:106997998:A:C	C402W	1.000
12:106997999:C:T	C402Y	1.000
12:106998009:A:G	W399R	1.000
12:106998009:A:T	W399R	1.000
12:106998015:A:G	W397R	1.000
12:106998015:A:T	W397R	1.000
12:106999568:A:G	W374R	1.000
12:106999568:A:T	W374R	1.000
12:106999579:A:G	L370P	1.000

dbSNP variants (sampled 300 via entrez): RS1000032990 (12:107042710 C>T), RS1000035465 (12:107025897 C>A,G), RS1000125244 (12:107090993 T>C), RS1000138675 (12:107053476 C>G,T), RS1000150036 (12:107029556 T>C), RS1000163118 (12:107069542 T>C), RS1000166814 (12:107063383 G>A,C), RS1000196085 (12:107004677 G>A,C), RS1000206679 (12:107025196 AT>A,ATT), RS1000249482 (12:107020272 T>C), RS1000262182 (12:107063625 C>T), RS1000292383 (12:107082306 A>C), RS1000333536 (12:107055072 T>A), RS1000350200 (12:107013750 A>G), RS1000378166 (12:107014028 G>A)

Disease associations

OMIM: gene MIM:601933 | disease phenotypes: MIM:614163

GenCC curated gene-disease

Mondo (3): attention deficit-hyperactivity disorder (MONDO:0007743), circadian rhythm sleep disorder, delayed sleep phase type (MONDO:0024377), delayed sleep phase syndrome, susceptibility to (MONDO:0800001)

Orphanet (0):

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0031354	Sleep onset insomnia

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST007565_26	Morning person	1.000000e-13
GCST012279_10	Suicide attempt severity in mood disorders	9.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement
EFO:0006882	suicide behaviour measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4296246 (SINGLE PROTEIN), CHEMBL4296247 (PROTEIN FAMILY)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs8192440	Efficacy	3	lithium	Bipolar Disorder

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1861591	CRY1		0.00	0
rs8192440	CRY1	3	0.00	1	lithium

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — Circadian clock proteins

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
KL044	Binding	7.2	pEC50

ChEMBL bioactivities

252 potent at pChembl≥5 of 256 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.96	EC50	11	nM	CHEMBL4277833
7.70	EC50	20	nM	CHEMBL4288250
7.68	EC50	21	nM	CHEMBL4286916
7.64	EC50	23	nM	CHEMBL4286923
7.60	EC50	25	nM	CHEMBL4290598
7.55	EC50	28	nM	CHEMBL4279225
7.54	EC50	29	nM	CHEMBL3753839
7.51	EC50	31	nM	CHEMBL4289135
7.50	EC50	32	nM	CHEMBL4293352
7.48	EC50	33	nM	CHEMBL3753932
7.47	EC50	34	nM	CHEMBL4292685
7.46	EC50	35	nM	CHEMBL4277275
7.46	EC50	35	nM	CHEMBL3752819
7.46	EC50	35	nM	CHEMBL3752502
7.43	EC50	37	nM	CHEMBL4287967
7.40	EC50	40	nM	CHEMBL4288718
7.39	EC50	41	nM	CHEMBL4294270
7.38	EC50	42	nM	CHEMBL4289790
7.36	EC50	44	nM	CHEMBL4286068
7.35	EC50	45	nM	CHEMBL4283783
7.34	EC50	46	nM	CHEMBL4281214
7.30	EC50	50	nM	CHEMBL4290327
7.29	EC50	51	nM	CHEMBL4292041
7.28	EC50	53	nM	CHEMBL4290336
7.24	EC50	57	nM	CHEMBL4283668
7.23	EC50	59	nM	CHEMBL4277829
7.14	EC50	73	nM	CHEMBL4284123
7.12	EC50	76	nM	CHEMBL4287301
7.11	EC50	78	nM	CHEMBL4292482
7.10	EC50	80	nM	CHEMBL4278290
7.10	EC50	79	nM	CHEMBL4280285
7.09	EC50	81	nM	CHEMBL4277405
7.08	EC50	83	nM	CHEMBL4281175
7.08	EC50	84	nM	CHEMBL4285073
7.07	EC50	86	nM	CHEMBL4278653
7.05	EC50	90	nM	CHEMBL1446115
7.02	EC50	95	nM	CHEMBL4284237
7.00	EC50	100	nM	CHEMBL3752323
7.00	EC50	100	nM	CHEMBL3753078
7.00	EC50	100	nM	CHEMBL1487843
6.95	EC50	113	nM	CHEMBL4284751
6.91	EC50	123	nM	CHEMBL3752018
6.90	EC50	125	nM	CHEMBL4292764
6.90	EC50	127	nM	CHEMBL4281572
6.89	EC50	128	nM	CHEMBL3753693
6.83	EC50	149	nM	CHEMBL4294461
6.83	EC50	147	nM	CHEMBL4287552
6.83	EC50	147	nM	CHEMBL4291869
6.83	EC50	148	nM	CHEMBL4280376
6.82	EC50	150	nM	CHEMBL4291499

CTD chemical–gene interactions

62 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	increases expression, decreases reaction	4
Air Pollutants	increases expression, decreases expression, affects cotreatment, increases abundance	3
Hydrogen Peroxide	affects cotreatment, affects expression, affects reaction, decreases expression	3
Valproic Acid	affects expression, decreases methylation, increases expression	3
Cyclosporine	decreases expression, increases expression	3
Particulate Matter	decreases expression, increases abundance, increases expression, increases methylation	3
KL001	increases stability, affects binding, decreases reaction, increases expression, decreases expression (+1 more)	2
Benzo(a)pyrene	increases expression, increases methylation	2
Doxorubicin	decreases expression, increases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
GSK-J4	increases expression	1
alpha-pinene	increases abundance, affects cotreatment, increases expression	1
bisphenol A	decreases expression	1
trichostatin A	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression, increases abundance	1
cobaltous chloride	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
methacrylaldehyde	increases abundance, affects cotreatment, increases expression	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, affects expression, affects reaction	1
gallocatechol	affects cotreatment, affects expression, affects reaction	1
epicatechin gallate	affects cotreatment, affects expression, affects reaction	1
di-n-butylphosphoric acid	affects expression	1
cylindrospermopsin	increases expression	1
CPG-oligonucleotide	increases expression	1
abrine	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4257307	Binding	Modulation of C-terminal FLAG3-taged CRY1 (unknown origin) expressed in HEK293 cells incubated for 24 hrs measured every 7.5 mins for 1 hr by luciferase reporter gene assay	Carbazole-containing sulfonamides as cryptochrome modulators

Cellosaurus cell lines

4 cell lines: 3 embryonic stem cell, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A0S9	SEES3-1V human CRY1, clone1	Embryonic stem cell	Male
CVCL_A0T0	SEES3-1V human CRY1, clone2	Embryonic stem cell	Male
CVCL_A0T1	SEES3-1V human CRY1, clone3	Embryonic stem cell	Male
CVCL_B1PB	Abcam HeLa CRY1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00152750	PHASE4	UNKNOWN	Study of Clonidine on Sleep Architecture in Children With Tourette’s Syndrome (TS) and Comorbid ADHD
NCT00181571	PHASE4	COMPLETED	A Double-Blind Comparison of Concerta and Placebo in Adults With Attention Deficit Hyperactivity Disorder
NCT00181675	PHASE4	COMPLETED	A Double-Blind Comparison of Galantamine HBr and Placebo in Adults With Attention Deficit Hyperactivity Disorder
NCT00181714	PHASE4	COMPLETED	Prevention of Cigarette Smoking in Attention Deficit Hyperactivity Disorder (ADHD) Youth With Concerta
NCT00181948	PHASE4	COMPLETED	Strattera Treatment in Children With ADHD Who Have Poor Response to Stimulant Therapy
NCT00181987	PHASE4	COMPLETED	Concerta in the Treatment of ADHD in Youth and Adults With Bipolar Disorder
NCT00190736	PHASE4	COMPLETED	Efficacy and Safety of Once-Daily Atomoxetine Hydrochloride in Adults With ADHD Over an Extended Period of Time (6 Months)
NCT00190775	PHASE4	COMPLETED	A Randomized, Double-Blind Comparison of Placebo and Atomoxetine Hydrochloride Given Once a Day in Adults With Attention-Deficit/Hyperactivity Disorder (ADHD)
NCT00190879	PHASE4	COMPLETED	Placebo-Controlled Study of Atomoxetine Hydrochloride in the Treatment of Adults With ADHD and Comorbid Social Anxiety Disorder
NCT00190957	PHASE4	COMPLETED	Atomoxetine Treatment of Adults With ADHD and Comorbid Alcohol Abuse
NCT00191035	PHASE4	COMPLETED	Maintenance of Benefit With Atomoxetine Hydrochloride in Adolescents With ADHD
NCT00191048	PHASE4	COMPLETED	Treatment With Atomoxetine Hydrochloride in Children and Adolescents With ADHD
NCT00191633	PHASE4	COMPLETED	Study of Atomoxetine in Children With ADHD to Assess Symptomatic and Functional Outcomes
NCT00191906	PHASE4	COMPLETED	Comparison of Atomoxetine and Placebo in Children With Attention-Deficit/Hyperactivity Disorder (ADHD) and/or Reading Disorder (RD)
NCT00216918	PHASE4	COMPLETED	Neuropsychological Functioning in Children With Attention-Deficit/Hyperactivity Disorder.
NCT00221962	PHASE4	COMPLETED	Study of Aripiprazole (Abilify) in Children With ADHD (Attention Deficit Hyperactivity Disorder)
NCT00223561	PHASE4	COMPLETED	Methylphenidate and Driving Ability in Adult Patients With Attention-Deficit Hyperactivity Disorder
NCT00299234	PHASE4	TERMINATED	Atomoxetine for Children With Acquired Attentional Disorders Following Completion of Chemotherapy for ALL
NCT00302406	PHASE4	COMPLETED	Naturalistic Substitution of Concerta in Adult Subject With ADHD Receiving Immediate Release Methylphenidate
NCT00305370	PHASE4	COMPLETED	Aripiprazole Associated With Methylphenidate in Children and Adolescents With Bipolar Disorder and ADHD
NCT00381758	PHASE4	COMPLETED	The COMACS Study: A Comparison of Methylphenidates in an Analog Classroom Setting
NCT00406354	PHASE4	COMPLETED	Comparison of Atomoxetine Versus Placebo in Children and Adolescents With ADHD and Comorbid ODD in Germany
NCT00434213	PHASE4	COMPLETED	Characterization of Dermal Reactions in Pediatric Patients With ADHD Using DAYTRANA
NCT00468143	PHASE4	COMPLETED	A Within-Subject Cross-Over Comparison Between Immediate Release and Extended Release Adderall
NCT00471354	PHASE4	COMPLETED	A Study for Patients With Attention-Deficit/Hyperactivity Disorder Treated With Atomoxetine
NCT00483106	PHASE4	COMPLETED	Clinical and Pharmacogenetic Study of Attention Deficit With Hyperactivity Disorder (ADHD)
NCT00485849	PHASE4	COMPLETED	A Study of Atomoxetine for Attention Deficit and Hyperactive/Impulsive Behaviour Problems in Children With ASD
NCT00485875	PHASE4	COMPLETED	Safety and Efficacy of Switching From a Stimulant Medication to Atomoxetine in Children and Adolescents With ADHD
NCT00486122	PHASE4	COMPLETED	Evaluation of Continuous Symptom Treatment of ADHD
NCT00500071	PHASE4	COMPLETED	Dose-Optimization Study Evaluating the Efficacy, Safety and Tolerability of Vyvanse (Lisdexamfetamine Dimesylate) in Children Aged 6-12 Diagnosed With ADHD
NCT00506727	PHASE4	COMPLETED	Analog Classroom Study Comparison of ADDERALL XR With STRATTERA in Children Aged 6-12 With ADHD
NCT00510276	PHASE4	COMPLETED	Treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) With Atomoxetine in Young Adults and Its Effects on Functional Outcomes
NCT00517504	PHASE4	COMPLETED	Methylphenidate Study in Young Children With Developmental Disorders
NCT00517647	PHASE4	COMPLETED	Atomoxetine Pilot Study in Preschool Children With ADHD
NCT00518232	PHASE4	COMPLETED	A Study to Determine Effective and Tolerable Titration Scheme for OROS-Methylphenidate in Children With Attention-deficit Hyperactivity Disorder
NCT00530257	PHASE4	COMPLETED	Study of the Effects of Osmotic-Release Oral System (OROS) Methylphenidate (Concerta) on Attention and Memory
NCT00536419	PHASE4	UNKNOWN	Impact of Attention Deficit/Hyperactivity Disorder and Substance Use Disorder on Motorcycle Traffic Accidents
NCT00546910	PHASE4	COMPLETED	Comparison of Atomoxetine Versus Placebo in Children With Attention-Deficit/Hyperactivity Disorder (ADHD)
NCT00552266	PHASE4	UNKNOWN	Methylphenidate in ADHD With Trichotillomania
NCT00564954	PHASE4	COMPLETED	A Study of Dex-methylphenidate Extended Release in Children (6-12 Years) With Attention-Deficit/Hyperactivity Disorder (ADHD)