Table 1.
Non-exhaustive list of studied human clock genes, expressed proteins, their main function and associated psychiatric disorders
| Gene | Nomenclature and protein | Protein function | Associated disorder |
|---|---|---|---|
| Clock | Circadian Locomotor Output Cycles Kaput (CLOCK) | Positive regulation of period and timeless genes through interaction with BMAL-1 | MDD [47-49] BD [16,48,50–53] SCH [14,54*] |
| Timeless | Timeless homolog (TIM) | Negative regulation of CLOCK-BMAL-1 activity through interaction with PER and close the circadian feedback loop | MDD [55,56] BD [55,57,58] |
| Cry-1 | Cryptochrome-1 (CRY-1) | Inhibition of CLOCK-BMAL-1 | MDD [48,59] BD [48] SCH [60] ANX [61] |
| Cry-2 | Cryptochrome-2 (CRY-2) | Inhibition of CLOCK-BMAL-1 | ANX [61,62] |
| Per-1 | Period homolog 1 (PER-1) | Negative regulation of CLOCK-BMAL-1 activity through interaction with CRY and close the circadian feedback loop | BD [51] SCH [63,64] ANX [65] |
| Per-2 | Period homolog 2 (PER-2) | Negative regulation of CLOCK-BMAL-1 activity through interaction with CRY and close the circadian feedback loop | MDD [48,66,67] BD [51] SCH [60,64,68] |
| Per-3 | Period homolog 3 (PER-3) | Seems not to have a critical role circadian rhythm. Contribute to determination of diurnal preference | MDD [48,49,69,70] BD [57,71-75] SCH [64] |
| Bmal-1 (or ARNTL-1) | Brain muscle ARNT like protein-1 (Aryl Hydrocarbon Receptor Nuclear Translocator like-1) (BMAL-1/ARNTL-1) | Positive regulation of period and timeless genes through interaction with CLOCK | MDD [48,55,67] BD [48,72,76] |
| Bmal-2 | Brain muscle ARNT like protein-2 | Probably has a role in activation of CLOCK and CLOCK-controlled genes | MDD [48,49,67] BD [48,51] SCH [64] |
| Npas-2 | Neuronal PAS domain protein-2 (NPAS-2) | Intrinsic enhancer for pre-mRNA splicing | MDD [48,55,78] BD [51,79,80] |
| Nr1d-1 (or Rev-erb-α) | Nuclear receptor subfamily-1, group d, member 1 (or orphan nuclear receptor REV-ERB-α) (NR1D1/REV-ERB-α) | Works as nuclear hormone receptors. | |
| Compete with RORA for binding to the BMAL-1 promoter and repress the BMAL-1 | |||
| Rora | Retinoid-related orphan receptor a (RORA) | Works as nuclear hormone receptors. | MDD [55,66,70] BD [58,81,82] |
| Compete with NR1D1 for binding to the BMAL-1 promoter and activate the BMAL-1 | |||
| Rorb | Retinoid-related orphan receptor b (RORB) | Works as nuclear hormone receptors. | BD [82,83] |
| Compete with NR1D1 for binding to the BMAL-1 promoter and activate the BMAL-1 | |||
| Dbp | D site of albumın promoter bındıng protein | Being regulated by CLOCK-BMAL-1 and CRY-1. | MDD [48] BD [50] |
| Supports the rhythmic transcription of downstream genes | |||
| Asmt | Acetylserotonin methyltransferase | The last enzyme of the melatonin synthesis pathway | MDD [84,85] BD [86,87] |
| Mtnr1-B | Melatonin receptor 1b | G protein coupled melatonin reseptor | MDD [88] |
| Aanat | Arylalkylamine N-acetyltransferase | The first enzyme of the melatonin synthesis pathway | MDD [48] |
| Csnk-1ε | Casein kinase 1 epsilon (CSNK1ε) | Phosphorylates of PER, CRY and BMAL, increases their degradation | MDD [55] BD [50,89,90] SCH [90,91] |
| Csnk-1δ | Casein kinase 1 delta (CSNK1δ) | Phosphorylates of PER, CRY and BMAL, increases their degradation | BD [51,90] SCH [90] |
| Regulation circadian period length | |||
| GSK-3β | Glycogen synthase kinase-3β (GSK-3β) | Regulation circadian period length | BD [92,93] |
*
CLOCK T3111C polymorphism.
MDD: major depressive disorder, BD: bipolar disorder, SCH: schizophrenia, ANX: anxiety disorders