Phenotypes associated with this allele

• Allele Symbol: Ryr2^tm1Slh
• Allele Name: targeted mutation 1, Susan L Hamilton
• Allele ID: MGI:3665257
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
ht1	Ryr2^tm1Slh/Ryr2^+	involves: 129S7/SvEvBrd	MGI:4359617
ht2	Ryr2^tm1Slh/Ryr2^+	involves: 129S7/SvEvBrd * C57BL/6	MGI:3689179
ht3	Ryr2^tm1Slh/Ryr2^+	involves: 129S7/SvEvBrd * C57BL/6J	MGI:6278119

Genotype
MGI:4359617

ht1

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

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

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

Genotype
MGI:3689179

ht2

• 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

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:6278119

ht3

• 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

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

• seizure activity is rare

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