Phenotypes associated with this allele

• Allele Symbol: Ryr2⁺
• Allele Name: wild type
• Allele ID: MGI:2432673
• Summary: 19 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
ht1	Ryr2^tm1.1Clhh/Ryr2^+	129S/SvEv-Ryr2^tm1.1Clhh	MGI:5432114
ht2	Ryr2^tm2Amks/Ryr2^+	B6.129-Ryr2^tm2Amks	MGI:3803484
ht3	Ryr2^tm1.1Maya/Ryr2^+	C57BL/6J-Ryr2^tm1.1Maya	MGI:4443207
ht4	Ryr2^tm1b(KOMP)Wtsi/Ryr2^+	C57BL/6N-Ryr2^tm1b(KOMP)Wtsi/H	MGI:5757672
ht5	Ryr2^tm2Hhv/Ryr2^+	involves: 129 * C57BL/6	MGI:5583981
ht6	Ryr2^em1Swch/Ryr2^+	involves: 129 * C57BL/6	MGI:6682030
ht7	Ryr2^tm4.1Amks/Ryr2^+	involves: 129 * C57BL/6	MGI:5582594
ht8	Ryr2^tm3.1Swch/Ryr2^+	involves: 129S1/Sv * 129X1/SvJ	MGI:5606048
ht9	Ryr2^tm2Amks/Ryr2^+	involves: 129S1/Sv * 129X1/SvJ	MGI:5582595
ht10	Ryr2^tm2.1Swch/Ryr2^+	involves: 129S1/Sv * 129X1/SvJ * Black Swiss	MGI:5605478
ht11	Ryr2^tm1.1Swch/Ryr2^+	involves: 129S1/Sv * 129X1/SvJ * Black Swiss	MGI:5285545
ht12	Ryr2^tm1.1Msnr/Ryr2^+	involves: 129S6/SvEvTac * FVB/N	MGI:3714032
ht13	Ryr2^tm1Slh/Ryr2^+	involves: 129S7/SvEvBrd	MGI:4359617
ht14	Ryr2^tm1Slh/Ryr2^+	involves: 129S7/SvEvBrd * C57BL/6	MGI:3689179
ht15	Ryr2^tm3.1Hhv/Ryr2^+	involves: 129S7/SvEvBrd * C57BL/6	MGI:6104247
ht16	Ryr2^tm1Slh/Ryr2^+	involves: 129S7/SvEvBrd * C57BL/6J	MGI:6278119
ht17	Ryr2^tm1Sgp/Ryr2^+	involves: 129/Sv * C57BL/6	MGI:3653876
ht18	Ryr2^tm3.1Amks/Ryr2^+	involves: C57BL/6	MGI:5582593
ht19	Ryr2^tm2.1Maya/Ryr2^+	involves: C57BL/6J	MGI:5432935

Genotype
MGI:5432114

ht1

• Allelic Composition: Ryr2^tm1.1Clhh/Ryr2⁺
• Genetic Background: 129S/SvEv-Ryr2^tm1.1Clhh

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

cardiovascular system

ventricular tachycardia ( J:186379 )

• non-sustained with programmed electrical stimulation

irregular heartbeat ( J:186379 )

• in the absence of isoproterenol and when regularly paced, mice exhibit few arrhythmogenic phenomena compared with wild-type mice

• when regularly paced, isoproterenol treated mice exhibit exacerbation of arrhythmogenicity compared with wild-type mice

abnormal myocardial fiber physiology ( J:186379 )

• cardiac myocytes treated with isoproterenol fail to exhibit ectopic calcium transient peaks or evoked responses with subsidiary calcium transient events unlike wild-type cells

muscle

abnormal myocardial fiber physiology ( J:186379 )

• cardiac myocytes treated with isoproterenol fail to exhibit ectopic calcium transient peaks or evoked responses with subsidiary calcium transient events unlike wild-type cells

Genotype
MGI:3803484

ht2

• Allelic Composition: Ryr2^tm2Amks/Ryr2⁺
• Genetic Background: B6.129-Ryr2^tm2Amks

mortality/aging

increased susceptibility to induced morbidity/mortality ( J:137696 )

• following strenuous exercise and catecholamine injection, mice exhibit sudden cardiac death unlike wild-type mice

• however, sudden cardiac death is not associated with seizures and treatment with S107 (a 1,4-benzothiazepine) can reduce this response to strenuous exercise and catecholamine injection

nervous system

nervous system phenotype ( J:137696 )

N • despite the occurrence of seizures, brain histology is normal

increased susceptibility to pharmacologically induced seizures ( J:137696 )

tonic-clonic seizures ( J:137696 )

• mice begin to exhibit spontaneous and recurrent seizures during weaning (P21 to P28)

• mice exhibit generalized clonic-tonic seizures in response to being placed in a new cage, woken from sleep or without any external stimuli

• seizures are associated with high-frequency calcium ion signaling and or burst activity

abnormal brain wave pattern ( J:137696 )

• during seizures, mice exhibit rapid spike discharges

cardiovascular system

ventricular tachycardia ( J:137696 )

• following strenuous exercise and catecholamine injection, mice exhibit ventricular tachycardia and sudden cardiac death unlike wild-type mice

abnormal myocardial fiber physiology ( J:137696 )

• cardiomyocytes stimulated with isoproterenol exhibit delayed afterdepolarizations between pacing cycles unlike in similarly treated wild-type mice that increases the depolarization rate from 1 Hz to 3 Hz and decreased coupling interval causing action potential fusion, incomplete repolarization, and spontaneous pacemaker activity

• cardiomyocytes treated with isoproterenol exhibit aberrant calcium ion transients between regular field-stimulated calcium ion transients that become self-sustaining unlike in similarly treated wild-type mice

increased response of heart to induced stress ( J:137696 )

• following strenuous exercise and catecholamine injection, mice exhibit ventricular tachycardia and sudden cardiac death unlike wild-type mice

• however, ventricular tachycardia and sudden cardiac death is not associated with seizures and treatment with S107 (a 1,4-benzothiazepine) can reduce these responses to strenuous exercise and catecholamine injection

• following strenuous exercise and catecholamine injection, mice exhibit an open probability that is higher than in sedentary mice that can be reversed with treatment with S107

behavior/neurological

increased susceptibility to pharmacologically induced seizures ( J:137696 )

tonic-clonic seizures ( J:137696 )

• mice begin to exhibit spontaneous and recurrent seizures during weaning (P21 to P28)

• mice exhibit generalized clonic-tonic seizures in response to being placed in a new cage, woken from sleep or without any external stimuli

• seizures are associated with high-frequency calcium ion signaling and or burst activity

homeostasis/metabolism

increased response of heart to induced stress ( J:137696 )

• following strenuous exercise and catecholamine injection, mice exhibit ventricular tachycardia and sudden cardiac death unlike wild-type mice

• however, ventricular tachycardia and sudden cardiac death is not associated with seizures and treatment with S107 (a 1,4-benzothiazepine) can reduce these responses to strenuous exercise and catecholamine injection

• following strenuous exercise and catecholamine injection, mice exhibit an open probability that is higher than in sedentary mice that can be reversed with treatment with S107

muscle

abnormal myocardial fiber physiology ( J:137696 )

• cardiomyocytes stimulated with isoproterenol exhibit delayed afterdepolarizations between pacing cycles unlike in similarly treated wild-type mice that increases the depolarization rate from 1 Hz to 3 Hz and decreased coupling interval causing action potential fusion, incomplete repolarization, and spontaneous pacemaker activity

• cardiomyocytes treated with isoproterenol exhibit aberrant calcium ion transients between regular field-stimulated calcium ion transients that become self-sustaining unlike in similarly treated wild-type mice

Genotype
MGI:4443207

ht3

• Allelic Composition: Ryr2^tm1.1Maya/Ryr2⁺
• Genetic Background: C57BL/6J-Ryr2^tm1.1Maya

cardiovascular system

ventricular tachycardia ( J:159451 )

• mice exhibit polymorphic ventricular premature contractions in response to light or sound unlike wild-type mice

• mice exposed to exercise or treatment with caffeine plus epinephrine exhibit bidirectional or polymorphic ventricular tachycardia unlike similarly treated wild-type mice

abnormal myocardial fiber physiology ( J:159451 )

• cardiomyocytes from mice treated with isoproterenol exhibit an 80% decline in peak cell shortening and prolonged calcium ion transient compared with cardiomyocytes form similarly treated wild-type mice

• before or after treatment with isoproterenol, sarcoplasmic reticulum calcium ion content is less than in cardiomyocytes from similarly treated wild-type mice

• before or after treatment with isoproterenol, calcium ion spark frequency is higher than in cardiomyocytes from similarly treated wild-type mice

• mice treated with 100 nmol/L isoproterenol exhibit higher frequencies of spontaneous calcium ion waves and increased full duration at half maximum compared with similarly treated wild-type mice

• cardiomyocytes exhibit decreased free diastolic sarcoplasmic reticulum calcium ions compared with wild-type cells

• however, luminal calcium ion levels reach the same baseline as in wild-type mice after caffeine treatment and treatment with dantrolene abolishes abnormal spontaneous after potentials and calcium ion transients following treatment with isoproterenol

• after isoproterenol treatment, cardiomyocytes exhibit spontaneous calcium ion transients and spontaneous after potentials unlike similarly treated wild-type cells

homeostasis/metabolism

increased physiological sensitivity to xenobiotic ( J:159451 )

• mice exposed to exercise or treatment with caffeine plus epinephrine exhibit bidirectional or polymorphic ventricular tachycardia unlike similarly treated wild-type mice

• cardiomyocytes from mice treated with isoproterenol exhibit a decrease in time from peak to 80% decline in cell shortening and prolonged calcium ion transient compared with cardiomyocytes form similarly treated wild-type mice

• mice treated with 100 nmol/L isoproterenol exhibit higher frequencies of spontaneous calcium ion waves and increased full duration at half maximum compared with similarly treated wild-type mice

• after isoproterenol treatment, cardiomyocytes exhibit spontaneous calcium ion transients and spontaneous after potentials unlike similarly treated wild-type cells

• however, treatment with dantrolene abolishes abnormal spontaneous after potentials and calcium ion transients following treatment with isoproterenol

behavior/neurological

behavior/neurological phenotype ( J:159451 )

N • unlike Ryr2^tm2Amks homozygotes, mice do not exhibit spontaneous seizures or increased susceptibility to pharmacologically induced seizures following treatment with 4-aminopyridine and caffeine compared with wild-type mice

muscle

abnormal myocardial fiber physiology ( J:159451 )

• cardiomyocytes from mice treated with isoproterenol exhibit an 80% decline in peak cell shortening and prolonged calcium ion transient compared with cardiomyocytes form similarly treated wild-type mice

• before or after treatment with isoproterenol, sarcoplasmic reticulum calcium ion content is less than in cardiomyocytes from similarly treated wild-type mice

• before or after treatment with isoproterenol, calcium ion spark frequency is higher than in cardiomyocytes from similarly treated wild-type mice

• mice treated with 100 nmol/L isoproterenol exhibit higher frequencies of spontaneous calcium ion waves and increased full duration at half maximum compared with similarly treated wild-type mice

• cardiomyocytes exhibit decreased free diastolic sarcoplasmic reticulum calcium ions compared with wild-type cells

• however, luminal calcium ion levels reach the same baseline as in wild-type mice after caffeine treatment and treatment with dantrolene abolishes abnormal spontaneous after potentials and calcium ion transients following treatment with isoproterenol

• after isoproterenol treatment, cardiomyocytes exhibit spontaneous calcium ion transients and spontaneous after potentials unlike similarly treated wild-type cells

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
catecholaminergic polymorphic ventricular tachycardia 1		DOID:0060675	OMIM:604772	J:159451

Genotype
MGI:5757672

ht4

• Allelic Composition: Ryr2^{tm1b(KOMP)Wtsi}/Ryr2⁺
• Genetic Background: C57BL/6N-Ryr2^{tm1b(KOMP)Wtsi}/H
• Cell Lines: EPD0585_3_C09

Data Sources

IMPC Data for Ryr2

behavior/neurological

increased startle reflex ( J:211773 )

IMPC - HAR

Genotype
MGI:5583981

ht5

• Allelic Composition: Ryr2^tm2Hhv/Ryr2⁺
• Genetic Background: involves: 129 * C57BL/6

cardiovascular system

abnormal cardiovascular system physiology ( J:212870 )

• the mutant type 2 ryanodine receptor channels show an increase in and widely variable open probability response to luminal calcium compared to wild-type channels which show a moderate response

• however, mice show normal cardiac morphology and functional echocardiogram at rest

irregular heartbeat ( J:212870 )

• hearts under beta-adrenergic stimulation produce more frequent arrhythmic episodes characterized by premature ventricular complexes and ventricular bigeminy

• mice intraperitoneally injected with epinephrine and caffeine show highly arrhythmic behavior, mostly premature ventricular complexes, bigeminy, or ventricular tachyarrhythmias

• optical mapping of the anterior ventricular epicardium following isoproterenol plus caffeine application, indicates multiple ventricular foci of arrhythmia

ventricular premature beat ( J:212870 )

• hearts under beta-adrenergic stimulation produce arrhythmic episodes characterized by premature ventricular complexes

abnormal myocardial fiber physiology ( J:212870 )

• ventricular myocytes subjected to a stress test (isoproterenol-stimulation) exhibit more frequent spontaneous calcium release events and have shorter latency, either partial or fully propagated, than wild-type myocytes

muscle

abnormal myocardial fiber physiology ( J:212870 )

• ventricular myocytes subjected to a stress test (isoproterenol-stimulation) exhibit more frequent spontaneous calcium release events and have shorter latency, either partial or fully propagated, than wild-type myocytes

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
catecholaminergic polymorphic ventricular tachycardia 1		DOID:0060675	OMIM:604772	J:212870

Genotype
MGI:6682030

ht6

• Allelic Composition: Ryr2^em1Swch/Ryr2⁺
• Genetic Background: involves: 129 * C57BL/6

cardiovascular system

abnormal heart echocardiography feature ( J:302151 )

• echocardiography shows a slightly reduced heart rate of about 10% and moderately increased (about 20%) left ventricular wall thickness

• however, ejection fraction, fractional shortening, stroke volume and cardiac output are unchanged

decreased heart rate ( J:302151 )

• heart rate is reduced about 10%

irregular heartbeat ( J:302151 )

• none of the common stimulation protocols (a burst pacing, a long pause, and a short-coupled premature ventricular complex) reliably induce ventricular arrhythmias in mutant mice

• however, a protocol consisting of a long-burst, long-pause, and short-coupled extra-stimulus (LBLPS) consistently triggers ventricular arrhythmias in mutants but not wild-type mice

• mice pretreated with quinidine sulfate reduces the duration and incidence of LBLPS-evoked polymorphic ventricular arrhythmias

abnormal myocardial fiber physiology ( J:302151 )

• elevating extracellular calcium concentration to promote sarcoplasmic reticulum calcium overload, induces little or no calcium waves in hearts

• hearts show resilience to caffeine- and epinephrine-promoted spontaneous calcium waves

• at high stimulation frequencies, hearts are more prone to calcium alternans and exhibit prolonged calcium release refractoriness

• however, the amplitude, time to peak, and decay time of depolarization-induced calcium transients at low stimulation frequency in hearts or isolated cardiomyocytes are similar to wild-type mice

• ventricular myocytes show an electrophysiological remodeling of surface membrane currents

• the Na/Ca exchange current is substantially augmented in ventricular myocytes

• the transient outward potassium current density and voltage-dependent activation are enhanced in ventricular myocytes

• ventricular myocytes are highly susceptible to early afterdepolarizations

abnormal myocardial fiber calcium currents ( J:302151 )

• L-type calcium channel current density in ventricular myocytes is enhanced

abnormal myocardial fiber sodium currents ( J:302151 )

• the sodium current shows a leftward (hyperpolarization) shift in voltage-dependent activation and inactivation in ventricular myocytes

decreased response of heart to induced stress ( J:302151 )

• a mixture of a high dose of caffeine and epinephrine does not promote ventricular arrhythmias as in wild-type mice, indicating protection of heart against stress-induced ventricular arrhythmias

homeostasis/metabolism

decreased response of heart to induced stress ( J:302151 )

• a mixture of a high dose of caffeine and epinephrine does not promote ventricular arrhythmias as in wild-type mice, indicating protection of heart against stress-induced ventricular arrhythmias

nervous system

abnormal action potential ( J:302151 )

• ventricular myocytes exhibit an altered action potential waveform with a shorter action potential duration at 50% and prolonged action potential duration at 90%, however the action potential amplitude and resting membrane potential are unchanged

muscle

abnormal myocardial fiber physiology ( J:302151 )

• elevating extracellular calcium concentration to promote sarcoplasmic reticulum calcium overload, induces little or no calcium waves in hearts

• hearts show resilience to caffeine- and epinephrine-promoted spontaneous calcium waves

• at high stimulation frequencies, hearts are more prone to calcium alternans and exhibit prolonged calcium release refractoriness

• however, the amplitude, time to peak, and decay time of depolarization-induced calcium transients at low stimulation frequency in hearts or isolated cardiomyocytes are similar to wild-type mice

• ventricular myocytes show an electrophysiological remodeling of surface membrane currents

• the Na/Ca exchange current is substantially augmented in ventricular myocytes

• the transient outward potassium current density and voltage-dependent activation are enhanced in ventricular myocytes

• ventricular myocytes are highly susceptible to early afterdepolarizations

abnormal myocardial fiber calcium currents ( J:302151 )

• L-type calcium channel current density in ventricular myocytes is enhanced

abnormal myocardial fiber sodium currents ( J:302151 )

• the sodium current shows a leftward (hyperpolarization) shift in voltage-dependent activation and inactivation in ventricular myocytes

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
heart disease		DOID:114		J:302151

Genotype
MGI:5582594

ht7

• Allelic Composition: Ryr2^tm4.1Amks/Ryr2⁺
• Genetic Background: involves: 129 * C57BL/6

cardiovascular system

abnormal myocardial fiber morphology ( J:212640 )

• leaky calcium channels in the sarcoplasmic reticulum of atrial myocytes

atrial fibrillation ( J:212640 )

• induced by atrial burst pacing in 5 of 14 mice

muscle

abnormal myocardial fiber morphology ( J:212640 )

• leaky calcium channels in the sarcoplasmic reticulum of atrial myocytes

abnormal sarcoplasmic reticulum morphology ( J:212640 )

• leaky calcium channels in the sarcoplasmic reticulum of atrial myocytes

cellular

abnormal sarcoplasmic reticulum morphology ( J:212640 )

• leaky calcium channels in the sarcoplasmic reticulum of atrial myocytes

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
catecholaminergic polymorphic ventricular tachycardia 1		DOID:0060675	OMIM:604772	J:212640

Genotype
MGI:5606048

ht8

• Allelic Composition: Ryr2^tm3.1Swch/Ryr2⁺
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ

cardiovascular system

abnormal myocardial fiber physiology ( J:215190 )

• the time-to-peak and time-to-50% decay of calcium release evoked by depolarization is slightly, but significantly, increased in cardiomyocytes

• however, mice do not exhibit stress-induced (by caffeine or epinephrine) ventricular tachyarrhythmias at young or older ages

muscle

abnormal myocardial fiber physiology ( J:215190 )

• the time-to-peak and time-to-50% decay of calcium release evoked by depolarization is slightly, but significantly, increased in cardiomyocytes

• however, mice do not exhibit stress-induced (by caffeine or epinephrine) ventricular tachyarrhythmias at young or older ages

Genotype
MGI:5582595

ht9

• Allelic Composition: Ryr2^tm2Amks/Ryr2⁺
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ

cardiovascular system

abnormal myocardial fiber morphology ( J:212640 )

• leaky calcium channels in the sarcoplasmic reticulum of atrial myocytes

• however, a 1,4-benzothiazepine (Rycal S107) prevents calcium leak

atrial fibrillation ( J:212640 )

• induced by atrial burst pacing in 7 of 10 mice

• however, a 1,4-benzothiazepine (Rycal S107) prevents atrial burst pacing-induced atrial fibrillation

muscle

abnormal myocardial fiber morphology ( J:212640 )

• leaky calcium channels in the sarcoplasmic reticulum of atrial myocytes

• however, a 1,4-benzothiazepine (Rycal S107) prevents calcium leak

abnormal sarcoplasmic reticulum morphology ( J:212640 )

• leaky calcium channels in the sarcoplasmic reticulum of atrial and, to a lesser extent, ventricular myocytes

• however, a 1,4-benzothiazepine (Rycal S107) prevents calcium leak

cellular

abnormal sarcoplasmic reticulum morphology ( J:212640 )

• leaky calcium channels in the sarcoplasmic reticulum of atrial and, to a lesser extent, ventricular myocytes

• however, a 1,4-benzothiazepine (Rycal S107) prevents calcium leak

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
catecholaminergic polymorphic ventricular tachycardia 1		DOID:0060675	OMIM:604772	J:212640

Genotype
MGI:5605478

ht10

• Allelic Composition: Ryr2^tm2.1Swch/Ryr2⁺
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * Black Swiss

cardiovascular system

abnormal cardiovascular system physiology ( J:214434 )

• elevation of extracellular calcium or application of isoproterenol results in very few or no calcium waves in intact hearts unlike in wild-type mice which show increased frequency of spontaneous calcium waves

abnormal cardiac muscle contractility ( J:214434 )

• the L-type calcium channel current in cardiomyocytes is increased, resulting in a reduced excitation-contraction coupling gain

• the time to the peak of the calcium transient is increased in cardiomyocytes, whereas late decay times are shorter

• however, the rate of decay of caffeine-induced calcium transients is not different from wild-type cardiomyocytes

abnormal myocardial fiber physiology ( J:214434 )

• cardiomyocytes exhibit reduced propensity for spontaneous store overload-induced calcium release (SOICR)

• sarcoplasmic reticulum calcium content is greater in cardiomyocytes than in wild-type cells when bathed at 5 mM extracellular calcium to overload the sarcoplasmic reticulum, however sarcoplasmic reticulum calcium content under nonoverload conditions is not affected

muscle

abnormal cardiac muscle contractility ( J:214434 )

• the L-type calcium channel current in cardiomyocytes is increased, resulting in a reduced excitation-contraction coupling gain

• the time to the peak of the calcium transient is increased in cardiomyocytes, whereas late decay times are shorter

• however, the rate of decay of caffeine-induced calcium transients is not different from wild-type cardiomyocytes

abnormal myocardial fiber physiology ( J:214434 )

• cardiomyocytes exhibit reduced propensity for spontaneous store overload-induced calcium release (SOICR)

• sarcoplasmic reticulum calcium content is greater in cardiomyocytes than in wild-type cells when bathed at 5 mM extracellular calcium to overload the sarcoplasmic reticulum, however sarcoplasmic reticulum calcium content under nonoverload conditions is not affected

Genotype
MGI:5285545

ht11

• Allelic Composition: Ryr2^tm1.1Swch/Ryr2⁺
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * Black Swiss

cardiovascular system

ventricular tachycardia ( J:174541 )

• mice treated with caffeine and epinephrine exhibit increased ventricular compared with similarly treated wild-type mice

homeostasis/metabolism

increased physiological sensitivity to xenobiotic ( J:174541 )

• mice treated with caffeine and epinephrine exhibit increased ventricular compared with similarly treated wild-type mice

Genotype
MGI:3714032

ht12

• Allelic Composition: Ryr2^tm1.1Msnr/Ryr2⁺
• Genetic Background: involves: 129S6/SvEvTac * FVB/N

cardiovascular system

abnormal heart morphology ( J:122033 )

• small decrease in the cross-sectional area of septal and left ventricular cadiomyocytes

enlarged heart ( J:122033 )

• at day 1, mice have a slightly higher ratio of heart weight to body weight compared with wild-type

• however, at day 7 and 10 heart to body weight ratios are normal

growth/size/body

enlarged heart ( J:122033 )

• at day 1, mice have a slightly higher ratio of heart weight to body weight compared with wild-type

• however, at day 7 and 10 heart to body weight ratios are normal

Genotype
MGI:4359617

ht13

• Allelic Composition: Ryr2^tm1Slh/Ryr2⁺
• Genetic Background: involves: 129S7/SvEvBrd

cardiovascular system

irregular heartbeat ( J:152544 )

• atrial pacing using atrial burst results in increased ectopic beats and reentry compared to in similarly treated wild-type mice

abnormal myocardial fiber physiology ( J:152544 )

• atria myocyte exhibit increased sarcoplasmic reticulum calcium ion leak compared with wild-type cells

abnormal response of heart to induced stress ( J:152544 )

• mice are more susceptible to pacing-induced atrial fibrillation compared with similarly treated wild-type mice

• however, the increased susceptibility to pacing-induced atrial fibrillation can be rescued by over-expression of Adcy3 inhibitory peptide

homeostasis/metabolism

abnormal response of heart to induced stress ( J:152544 )

• mice are more susceptible to pacing-induced atrial fibrillation compared with similarly treated wild-type mice

• however, the increased susceptibility to pacing-induced atrial fibrillation can be rescued by over-expression of Adcy3 inhibitory peptide

muscle

abnormal myocardial fiber physiology ( J:152544 )

• atria myocyte exhibit increased sarcoplasmic reticulum calcium ion leak compared with wild-type cells

Genotype
MGI:3689179

ht14

• Allelic Composition: Ryr2^tm1Slh/Ryr2⁺
• Genetic Background: involves: 129S7/SvEvBrd * C57BL/6

Ryr2^tm1Slh/Ryr⁺ MRI heart images

cardiovascular system

decreased cardiac muscle contractility ( J:111780 )

• systolic function is modestly reduced as demonstrated by decreased peak of aortic velocity

decreased heart right ventricle muscle contractility ( J:111780 )

• exhibit a lowered right ventricular end-diastolic volume and higher right ventricular end-diastolic pressure, indicating restrictive ventricular filling, however show no evidence of fibrofatty infiltration or arrhythmogenic right ventricular dysplasia

ventricular tachycardia ( J:111780 )

• develop ventricular tachycardia after caffeine and epinephrine injection or with programmed ventricular stimulation

ventricular premature beat ( J:111780 )

• multiple premature ventricular beats are seen after isoproterenol treatment (a beta-adrenergic receptor agonist), however no sustained ventricular arrhythmias are seen

abnormal myocardial fiber physiology ( J:111780 )

• isolated cardiomyocytes exhibit a higher incidence of spontaneous calcium oscillations in the absence and presence of isoproterenol

cardiomyopathy ( J:111780 )

muscle

decreased cardiac muscle contractility ( J:111780 )

• systolic function is modestly reduced as demonstrated by decreased peak of aortic velocity

decreased heart right ventricle muscle contractility ( J:111780 )

• exhibit a lowered right ventricular end-diastolic volume and higher right ventricular end-diastolic pressure, indicating restrictive ventricular filling, however show no evidence of fibrofatty infiltration or arrhythmogenic right ventricular dysplasia

abnormal myocardial fiber physiology ( J:111780 )

• isolated cardiomyocytes exhibit a higher incidence of spontaneous calcium oscillations in the absence and presence of isoproterenol

cardiomyopathy ( J:111780 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
catecholaminergic polymorphic ventricular tachycardia 1		DOID:0060675	OMIM:604772	J:111780

Genotype
MGI:6104247

ht15

• Allelic Composition: Ryr2^tm3.1Hhv/Ryr2⁺
• Genetic Background: involves: 129S7/SvEvBrd * C57BL/6

cardiovascular system

decreased heart rate ( J:220671 )

• bradycardia at baseline

• however, mice exhibit normal fractional shortening and ejection fraction and show no gross structural alterations of the heart

ventricular fibrillation ( J:220671 )

• increasing the extracellular calcium concentration from 1.8 to 3.6 mM during adrenergic stress induces spontaneous long-lasting ventricular fibrillation

• however, hearts stimulated with isoproterenol do not show spontaneous arrhythmias under basal conditions and hearts stimulated with isoproterenol and administered caffeine fail to induce arrhythmias

abnormal myocardial fiber physiology ( J:220671 )

• the maximum rise rate and amplitude of the evoked intracellular calcium transient are depressed in ventricular myocytes, resulting in a lower e-c coupling gain

• ventricular myocytes show random occurrence of early afterdepolarizations which appear as depolarized potentials and distort the action potential waveform

• intracellular calcium transients are altered, showing random occurrence of a sustained, low-amplitude phase of calcium release

• high variability in intracellular calcium transient decay in ventricular myocytes

• in isoproterenol-stimulated ventricular myocytes, peak of calcium release during systole is decreased, gradually overloading the sarcoplasmic reticulum with calcium

muscle

abnormal myocardial fiber physiology ( J:220671 )

• the maximum rise rate and amplitude of the evoked intracellular calcium transient are depressed in ventricular myocytes, resulting in a lower e-c coupling gain

• ventricular myocytes show random occurrence of early afterdepolarizations which appear as depolarized potentials and distort the action potential waveform

• intracellular calcium transients are altered, showing random occurrence of a sustained, low-amplitude phase of calcium release

• high variability in intracellular calcium transient decay in ventricular myocytes

• in isoproterenol-stimulated ventricular myocytes, peak of calcium release during systole is decreased, gradually overloading the sarcoplasmic reticulum with calcium

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
catecholaminergic polymorphic ventricular tachycardia 1		DOID:0060675	OMIM:604772	J:220671

Genotype
MGI:6278119

ht16

• Allelic Composition: Ryr2^tm1Slh/Ryr2⁺
• Genetic Background: involves: 129S7/SvEvBrd * C57BL/6J

behavior/neurological

increased susceptibility to pharmacologically induced seizures ( J:235432 )

• juvenile mice show increased susceptibility to 4-aminopyridine induced seizures and to seizure-induced lethality, likely due to hypoxia/hypoxemia resulting from peri-ictal cardiorespiratory instability and a lower threshold for spreading depolarization and to seizure-induced lethality, likely due to hypoxia/hypoxemia resulting from peri-ictal cardiorespiratory instability and a lower threshold for spreading depolarization

mortality/aging

increased susceptibility to induced morbidity/mortality ( J:235432 )

• all mice injected with a high dose of caffeine die within 2 hours of post-injection, indicating caffeine-induced lethal cardiac arrhythmias

• 71% of mice die shortly after 4-aminopyridine-induced seizures

cardiovascular system

decreased heart rate ( J:235432 )

• 3 of 5 mice show spontaneous episodes of bradycardia and artrioventricular block

irregular heartbeat ( J:235432 )

• lethal cardiac arrhythmias occur after seizures are induced

ventricular fibrillation ( J:235432 )

• mice injected with a high dose of caffeine show abnormal EKG patterns characterized by frequent bigeminy and sporadic ventricular fibrillation

atrioventricular block ( J:235432 )

• 3 of 5 mice show spontaneous episodes of bradycardia and artrioventricular block

abnormal heart electrocardiography waveform feature ( J:235432 )

• prolonged EEG-EKG monitoring indicates spontaneous bilateral cortical epileptiform spike discharges

• mice injected with a high dose of caffeine show abnormal EKG patterns characterized by frequent bigeminy and sporadic ventricular fibrillation

nervous system

increased susceptibility to pharmacologically induced seizures ( J:235432 )

• juvenile mice show increased susceptibility to 4-aminopyridine induced seizures and to seizure-induced lethality, likely due to hypoxia/hypoxemia resulting from peri-ictal cardiorespiratory instability and a lower threshold for spreading depolarization and to seizure-induced lethality, likely due to hypoxia/hypoxemia resulting from peri-ictal cardiorespiratory instability and a lower threshold for spreading depolarization

abnormal nervous system electrophysiology ( J:235432 )

• mice show lowered threshold for spreading depolarization in the neocortex and the brainstem dorsal medulla which leads to cardiorespiratory collapse

abnormal afterhyperpolarization ( J:235432 )

• pyramidal neurons show an increase in slow after-hyperpolarization following an evoked action potential train

• however, no differences in resting membrane potential, resistance, or action potential frequency to injected depolarizing currents are seen

abnormal brain wave pattern ( J:235432 )

• prolonged EEG-EKG monitoring indicates spontaneous bilateral cortical epileptiform spike discharges

• abnormal spike discharges are mostly absent when mice are behaviorally active and increase at rest

• seizure activity is rare

abnormal brain theta wave pattern ( J:235432 )

• cortical theta power (4-7Hz) is increased during spike-frequent periods compared to spike-free periods

abnormal miniature excitatory postsynaptic currents ( J:235432 )

• mean miniature excitatory postsynaptic current (mEPSC) amplitude is larger in cortical layer II/III neurons, however frequency is not different

• mEPSC amplitude is increased in dorsal motor vagal neurons, however the mean frequency is unchanged

• however, layer II/III pyramidal neurons show normal spontaneous excitatory postsynaptic current frequency and amplitude

decreased paired-pulse ratio ( J:235432 )

• the paired pulse ratio is reduced and less variable in pyramidal neurons

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
catecholaminergic polymorphic ventricular tachycardia 1		DOID:0060675	OMIM:604772	J:235432

Genotype
MGI:3653876

ht17

• Allelic Composition: Ryr2^tm1Sgp/Ryr2⁺
• Genetic Background: involves: 129/Sv * C57BL/6

cardiovascular system

cardiovascular system phenotype ( J:109683 )

N • do not exhibit any macroscopic alteration of the heart and vessels, no fibrous-fatty infiltration, or right ventricular cardiomyopathy under normal basal conditions

ventricular tachycardia ( J:109683 )

• develop bidirectional and polymorphic ventricular tachycardia upon stress testing and on administration of caffeine and of adrenergic agonists

• 5 of 14 heterozygotes undergoing stress testing followed by epinephrine administration develop repetitive ventricular arrhythmias (sustained (VTsus) and non-sustained (VTns) ventricular tachycardia)

irregular heartbeat ( J:109683 )

• 4 of 8 (50%) heterozygotes undergoing epinephrine and caffeine treatment develop sustained arrhythmias and 5 of 5 heterozygotes pretreated with propranolol, an antiadrenergic compound, develop ventricular arrhythmias

ventricular fibrillation ( J:109683 )

• develop ventricular fibrillation on administration of caffeine and of adrenergic agonists

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
catecholaminergic polymorphic ventricular tachycardia 1		DOID:0060675	OMIM:604772	J:109683

Genotype
MGI:5582593

ht18

• Allelic Composition: Ryr2^tm3.1Amks/Ryr2⁺
• Genetic Background: involves: C57BL/6

cardiovascular system

abnormal myocardial fiber morphology ( J:212640 )

• leaky calcium channels in the sarcoplasmic reticulum of atrial myocytes

atrial fibrillation ( J:212640 )

• induced by atrial burst pacing in 9 of 15 mice

• however, a 1,4-benzothiazepine (Rycal S107) prevents atrial burst pacing-induced atrial fibrillation

muscle

abnormal myocardial fiber morphology ( J:212640 )

• leaky calcium channels in the sarcoplasmic reticulum of atrial myocytes

abnormal sarcoplasmic reticulum morphology ( J:212640 )

• leaky calcium channels in the sarcoplasmic reticulum of atrial myocytes

cellular

abnormal sarcoplasmic reticulum morphology ( J:212640 )

• leaky calcium channels in the sarcoplasmic reticulum of atrial myocytes

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
catecholaminergic polymorphic ventricular tachycardia 1		DOID:0060675	OMIM:604772	J:212640

Genotype
MGI:5432935

ht19

• Allelic Composition: Ryr2^tm2.1Maya/Ryr2⁺
• Genetic Background: involves: C57BL/6J

cardiovascular system

cardiovascular system phenotype ( J:186291 )

N • at rest, mice exhibit normal cardiac morphology and function

ventricular tachycardia ( J:186291 )

• mice exhibit bidirectional or polymorphic ventricular tachycardia (VT) induced by exercise or epinephrine unlike in wild-type mice

• pretreatment with K201 (JTV519) does not affect inducible VT

• however, dantrolene treatment rescues phenotype

abnormal myocardial fiber physiology ( J:186291 )

• cardiomyocytes exhibit reduced threshold of sarcoplasmic reticulum calcium load for channel activation compared with wild-type cells

muscle

abnormal myocardial fiber physiology ( J:186291 )

• cardiomyocytes exhibit reduced threshold of sarcoplasmic reticulum calcium load for channel activation compared with wild-type cells