Table 1.

Summary of the effects of circadian clock gene mutations on sleep and circadian rhythms.

Gene	Species	Manipulation or mutation	Region	Phenotype	Reference
Cry1/Cry2	Mouse	Double knockout	Global	Sleep rhythms abolished Increased NREM duration Higher sleep consolidation	[120]
Per1/Per2	Mouse	Double knockout	Global	Sleep rhythms abolished Sleep duration and homeostatic regulation intact	[121, 122]
Per2	Mouse	Human PER2 mutation associated with advanced sleep phase	Global	Shortened circadian period of activity	[139]
Per3	Mouse	Human PER3 mutation associated with changes in sleep timing and sleep rebound	Global	No change in sleep timing or amount Altered time course of EEG delta and theta power profiles during sleep rebound	[126]
Clock	Mouse	Δ19 mutation	Global	Reduced NREM duration	[123]
Clock	Mouse	Knockout	Excitatory cortical neurons	Seizures during NREM sleep	[129]
Npas2	Mouse	Knockout	Global	Altered NREM EEG Slowed sleep need accumulation and compromised REM recovery after sleep deprivation (SD) in females Compromised NREM recovery after SD in males	[124]
Timeless	Mouse	Human TIM mutation associated with advanced sleep phase	Global	Advanced phase of sleep-wake rhythms Altered responsiveness to light pulses	[141]
Bmal1	Mouse	Knockout	Global	Sleep rhythms abolished Sleep fragmentation Reduced homeostatic sleep response Increased total sleep time	[125]
Bmal1	Mouse	Knockout	Syt10-expressing neurons	Activity rhythms abolished	[130]
Bmal1	Mouse	Knockout	Forebrain neurons including SCN	Activity rhythms abolished	[131]
Bmal1	Mouse	Knockout	NMS SCN neurons	Activity rhythms abolished	[21]
Bmal1	Mouse	Knockout	VIP SCN neurons	Reduced amplitude of circadian rhythms of sleep	[132]
Bmal1	Mouse	Knockout	Forebrain neurons excluding SCN	Increased NREM during dark phase	[133]
Bmal1	Mouse	Knockout	VIP SCN neurons	Disrupted daily siesta	[162]
Bmal1	Mouse	Knockout	AVP SCN neurons	Loss of tissue-level Per2 expression rhythms in ex vivo SCN culture	[164]
Bmal1	Mouse	Knockout, rescue	Expression rescued in skeletal muscle	Recovery of normal sleep duration but not timing	[134]
PER2	Human	Missense mutation	Global	Advanced sleep phase syndrome (ASPS)	[138]
CRY2	Human	Missense mutation	Global	ASPS	[140]
TIMELESS	Human	Nonsense mutation	Global	ASPS	[141]
PER3	Human	Short length polymorphism	Global	Delayed sleep phase syndrome (DSPS)	[142]
PER3	Human	Longer length polymorphism	Global	Extreme morningness	[142]
CRY1	Human	Gain-of-function mutation	Global	DSPS	[143]