Phenotypes associated with this allele

• Allele Symbol: Scn5a⁺
• Allele Name: wild type
• Allele ID: MGI:2432061
• Summary: 8 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
ht1	Scn5a^tm1Care/Scn5a^+	FVB.129P2-Scn5a^tm1Care/Care	MGI:3769904
ht2	Scn5a^tm1Agrc/Scn5a^+	involves: 129	MGI:3641169
ht3	Scn5a^tm1Clhh/Scn5a^+	involves: 129 * 129S/SvEv * C57BL/6J	MGI:3765987
ht4	Scn5a^tm1.1Iba/Scn5a^+	involves: 129 * C57BL/6	MGI:6415595
ht5	Scn5a^tm1Agrc/Scn5a^+	involves: 129 * C57BL/6J	MGI:3621905
ht6	Scn5a^tm1Clhh/Scn5a^+	involves: 129/SvEv	MGI:5582068
ht7	Scn5a^em1Coop/Scn5a^+	involves: FVB/NJ	MGI:6415731
ht8	Scn5a^tm1Pec/Scn5a^+	involves: Swiss	MGI:3622652

Genotype
MGI:3769904

ht1

• Allelic Composition: Scn5a^tm1Care/Scn5a⁺
• Genetic Background: FVB.129P2-Scn5a^tm1Care/Care

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

mortality/aging

mortality/aging ( J:128657 )

N • unlike human patients with a similar mutation, heterozygotes do not display sudden cardiac death

cardiovascular system

decreased heart rate ( J:128657 )

• significantly slower heart rate

• flecainide induced extreme sinus bradycardia and/or sinus arrest in 4 of 6 mice compared to 0 of 6 in wild-type controls

abnormal impulse conducting system conduction ( J:128657 )

• epicardial mapping indicates slower conduction (increased activation time, reduced transverse conduction velocity) in the right ventricle but not in the left ventricle

prolonged PQ interval ( J:128657 )

• significant prolongation of the PQ interval

• increase in the flecainide-induced prolongation of the PQ interval compared to wild-type controls

prolonged QRS complex duration ( J:128657 )

• prolonged QRS duration

• increase in the flecainide-induced prolongation of the QRS interval compared to wild-type controls

prolonged QT interval ( J:128657 )

• prolonged QTc interval

abnormal sinoatrial node conduction ( J:128657 )

• more sinus pauses of longer duration

• however, no ventricular arrhythmias are detected

abnormal myocardial fiber physiology ( J:128657 )

• prolonged action potential duration at frequencies less than 4 Hz and smaller dV/dt(max) at all frequencies tested

• ventricular myocytes show reduced peak sodium current densities and prolonged current decay half-life (at voltages from -45 to -25 mV) at room temperature

• upstroke velocity (dV/dt(max)) of the elicited action potential is reduced by 31% at -120 mV

• the current density of persistent sodium currents is significantly larger at voltages between -90 and -10 mV

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Brugada syndrome 1		DOID:0110218	OMIM:601144	J:128657
long QT syndrome 3		DOID:0110646	OMIM:603830	J:128657

Genotype
MGI:3641169

ht2

• Allelic Composition: Scn5a^tm1Agrc/Scn5a⁺
• Genetic Background: involves: 129

cardiovascular system

cardiac fibrosis ( J:109689 )

• old but not young mutants show extensive fibrosis of the ventricular myocardium (in the left and right ventricular free walls and in the interventricular septum)

• although young mutants do not exhibit ventricular fibrosis, they do show increased perivascular fibrosis which becomes massive with age

decreased heart rate ( J:109689 )

• show slight but significant bradycardia

ventricular tachycardia ( J:166438 )

• mutants exhibit a higher incidence of ventricular tachycardia than wild-type (25% vs. 6%)

• ventricular tachycardias begin at earlier times in the right ventricular outflow tract than at the base of the left ventricle

• mutant hearts exhibit abnormal electrophysiological properties of the right ventricle at the right ventricle outflow tract, showing increased heterogeneities in action potential duration, ventricular effective refractory periods, electrogram duration ratios and response latencies that correlate with an increased incidence of discordant alternans and with steeper restitution slopes

abnormal impulse conducting system conduction ( J:109689 )

prolonged PR interval ( J:109689 )

• PR intervals progressively prolong with age (from 3 to 71 weeks)

prolonged P wave ( J:109689 )

• P-wave intervals progressively prolong with age (from 3 to 71 weeks)

prolonged QRS complex duration ( J:109689 )

• QRS intervals progressively prolong with age (from 3 to 71 weeks)

prolonged QT interval ( J:109689 )

• QTrc and QTc intervals are prolonged due to prolongation of the QRS interval

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Brugada syndrome 1		DOID:0110218	OMIM:601144	J:166438
progressive familial heart block type IA		DOID:0111074	OMIM:113900	J:109689

Genotype
MGI:3765987

ht3

• Allelic Composition: Scn5a^tm1Clhh/Scn5a⁺
• Genetic Background: involves: 129 * 129S/SvEv * C57BL/6J

mortality/aging

increased susceptibility to induced morbidity/mortality ( J:127879 )

• following tail clipping one mouse exhibited generalized seizure and died

• however, the lifespan of other mice is normal

postnatal lethality, incomplete penetrance ( J:127879 )

• fewer than expected mice are recovered 3 to 4 weeks after birth

cardiovascular system

ventricular tachycardia ( J:127879 )

• unlike in wild-type mice, application of programmed electrical stimulation induced ventricular tachycardia in 8 of 9 mice

irregular heartbeat ( J:127879 )

• electrogram duration (EGD) during programmed electrical stimulation parallels (PES) arrhythmic tendencies

• unlike in wild-type mice, propranolol fails to suppress arrhythmias following treatment with isoproterenol

• isoproterenol does not affect arrhythmia status during PES whereas in wild-type mice it induces arrhythmic effects

• mexiletine suppresses arrhythmias in 4 of 5 mice without effecting EGD

abnormal impulse conducting system conduction ( J:127879 )

• hearts exhibit greater increases in electrogram duration (EGD) than wild-type hearts during programmed electrical stimulation (PES)

• EGD during PES parallels arrhythmic tendencies

• mice exhibit greater stimulus to response latencies measured at the beginning of the PES sequences than do wild-type mice

• mice exhibit larger ventricular effective refractory period than wild-type mice (37+/-7 msec compared to 29+/-6 msec)

• unlike in wild-type mice, 1 uM propranolol accentuates the increase in EGD as S1S2 intervals are shortened

• treatment with propranolol increases EGD

abnormal myocardial fiber physiology ( J:127879 )

• action potential is prolonged in myocytes (152+/-17.8 msec compared to 55+/-6.6 msec in wild-type cells)

• unlike in wild-type mice, myocytes exhibit early afterdepolarization and persistent sodium tail currents

behavior/neurological

seizures ( J:127879 )

• following tail clipping one mouse exhibited generalized seizure and died

nervous system

seizures ( J:127879 )

• following tail clipping one mouse exhibited generalized seizure and died

Genotype
MGI:6415595

ht4

• Allelic Composition: Scn5a^tm1.1Iba/Scn5a⁺
• Genetic Background: involves: 129 * C57BL/6

mortality/aging

premature death ( J:266290 )

• high mortality at 5-7 weeks of age, with a median survival of 6.4 weeks

growth/size/body

increased heart weight ( J:266290 )

• heart weight/tibia length ratio is increased at 4 weeks of age

decreased body weight ( J:266290 )

• small, but significant, decrease in body weight at 2 and 4 weeks of age

increased lung weight ( J:266290 )

• lung weight/tibia length ratio is increased in 4 week old mice

• however, pulmonary congestion or edema are not seen

cardiovascular system

liver vascular congestion ( J:266290 )

• chronic congestive liver with blood stasis in the capillary vessels between centroglobular and periglobular veins

abnormal heart morphology ( J:266290 )

• the alpha-actinin 2 and t-tubule network are disorganized in the heart at 4, but not 2 weeks of age

increased myocardial fiber size ( J:266290 )

• cardiomyocyte hypertrophy as indicated by a larger cell capacitance

abnormal heart atrium morphology ( J:266290 )

• atria frequently contains organized thrombi

increased heart weight ( J:266290 )

• heart weight/tibia length ratio is increased at 4 weeks of age

thick ventricular wall ( J:266290 )

• larger left ventricular free-wall thickness at 10 weeks, but not 2 or 4 weeks of age

cardiac fibrosis ( J:266290 )

• small increase in left ventricular fibrosis

abnormal heart echocardiography feature ( J:266290 )

• echocardiography shows that the septum and left ventricle free wall thickness are larger

ventricular tachycardia ( J:266290 )

• about 30% of 2-week old and 50% of 3-4 week old mice exhibit spontaneous episodes of monomorphic and polymorphic premature ventricular beats and/or tachycardia

• the number of mice exhibiting tachyarrhythmias progressively decreases with aging, suggesting that most mice in sinus rhythm survive

irregular heartbeat ( J:266290 )

• most mice, even at 2 weeks of age, exhibit rhythm disorders, and only about 30% of 2-week old and about 20% of 3-week old mice are in sinus rhythm

• acute propranolol injection has no effect on incidence of arrhythmias

• acute ranolazine injection suppresses arrhythmias

ventricular fibrillation ( J:266290 )

• lethal ventricular fibrillation was seen in one 4-week old mouse

ventricular premature beat ( J:266290 )

• about 30% of 2-week old and 50% of 3-4 week old mice exhibit spontaneous episodes of monomorphic and polymorphic premature ventricular beats and/or tachycardia

atrioventricular block ( J:266290 )

• second-degree atrioventricular block, resulting from prolonged ventricular repolarization and refractoriness occurs in about 30% of mice

• the number of mice exhibiting atrioventricular block progressively decreases with aging, suggesting that most mice in sinus rhythm survive

prolonged QRS complex duration ( J:266290 )

• ventricular conduction as reflected by QRS interval is prolonged

• however, atrial and atrioventricular conduction is not altered and RR interval is normal

prolonged QT interval ( J:266290 )

• prolongation of QTc interval

• acute ranolazine injection decreases QTc interval, without affecting QRS duration

abnormal myocardial fiber physiology ( J:266290 )

• at 4 weeks, mice show intracellular calcium concentration transients with higher amplitude and slower kinetics (longer time-to-peak and decay times), combined with enhanced sarcoplasmic reticulum calcium load without alterations of decay time of the caffeine-evoked intracellular calcium transients

• percentage of cardiomyocytes exhibiting spontaneous calcium waves and frequency of calcium waves is increased with faster propagation speed, indicating impaired sarcoplasmic reticulum function

• however, no change in calcium wave amplitude is seen

• calcium sparks in cardiomyocytes are higher, wider, and longer

abnormal myocardial fiber sodium currents ( J:266290 )

• cardiomyocytes exhibit impaired Na⁺ current, with a shift of steady-state inactivation towards depolarized potentials and consequently increased window current and higher slow and fast time constants of inactivation

• however, recovery from inactivation is similar to controls

• the TTX-sensitive late Na⁺ current at the end of a 350-ms depolarizing step is much larger in cardiomyocytes

congestive heart failure ( J:266290 )

• 4-week old mice show some symptoms of congestive heart failure

liver/biliary system

liver vascular congestion ( J:266290 )

• chronic congestive liver with blood stasis in the capillary vessels between centroglobular and periglobular veins

muscle

increased myocardial fiber size ( J:266290 )

• cardiomyocyte hypertrophy as indicated by a larger cell capacitance

nervous system

abnormal action potential ( J:266290 )

• ventricular action potential duration is prolonged in 4 week old mice at a pacing cycle length of 200 ms

• ventricular preparations show a depolarized resting membrane potential and a lower action potential amplitude

• action potential prolongation is associated with the occurrence of early afterdepolarizations in 9 of 17 ventricular preparations

• resting membrane potential is depolarized and action potential durations prolonged in left atrial preparations

• ranolazine treatment shortens action potential duration and decreases early afterdepolarizations

respiratory system

increased lung weight ( J:266290 )

• lung weight/tibia length ratio is increased in 4 week old mice

• however, pulmonary congestion or edema are not seen

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
long QT syndrome 3		DOID:0110646	OMIM:603830	J:266290

Genotype
MGI:3621905

ht5

• Allelic Composition: Scn5a^tm1Agrc/Scn5a⁺
• Genetic Background: involves: 129 * C57BL/6J

cardiovascular system

abnormal heart rate ( J:76331 )

• after aortic cannulation and Langendorff-perfusion, whole isolated hearts show marked rate slowing

ventricular tachycardia ( J:76331 )

• display ventricular tachycardia during continuous pacing or after the delivery of S2 stimuli at shorter S1-S2 intervals

abnormal impulse conducting system conduction ( J:76331 )

• exhibit a 50% reduction in sodium conduction, leading to impaired action potential propagation and atrioventricular conduction, delayed intramyocardial conduction, increased ventricular refractoriness, and ventricular tachycardia with characteristics of reentrant excitation

prolonged PR interval ( J:76331 )

• prolonged PR interval, however QT interval is unchanged

prolonged P wave ( J:76331 )

abnormal myocardial fiber physiology ( J:76331 )

• peak current densities of myocytes are reduced, indicating reduced sodium channel density

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
progressive familial heart block type IA		DOID:0111074	OMIM:113900	J:76331

Genotype
MGI:5582068

ht6

• Allelic Composition: Scn5a^tm1Clhh/Scn5a⁺
• Genetic Background: involves: 129/SvEv

cardiovascular system

sinus bradycardia ( J:186583 )

• 6 of 10 mice under ketamine anesthesia show sinus bradycardia after pacing

abnormal impulse conducting system conduction ( J:186583 )

• electrocardiographic waveforms suggest depressed intra-atrial, atrioventricular node, and intraventricular conduction in the absence of sinoatrial exit block

• sinatrial preparations show depressed sinus rate, greater excitation latencies and slowed conduction velocities for the spread of excitation between the sinoatrial node and atrial septum

abnormal atrioventricular node conduction ( J:186583 )

• electrocardiographic waveforms suggest slow atrioventricular node conduction

atrioventricular block ( J:186583 )

• 4 of 10 mice under ketamine anesthesia show II to III atrioventricular block

prolonged PR interval ( J:186583 )

• mice under avertin anesthesia show longer PR intervals

prolonged QRS complex duration ( J:186583 )

• mice under avertin anesthesia show longer QRS durations

prolonged QT interval ( J:186583 )

• mice under avertin anesthesia show abnormal ventricular repolarization, seen as increased QT and corrected QT intervals (after correction for RR intervals) compared with wild-type mice

abnormal sinoatrial node conduction ( J:186583 )

• mice under ketamine or avertin anesthesia exhibit greater sinus node recovery times after a burst pacing protocol over a 30-second stimulation period, indicating depressed sinoatrial node pacemaker function

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
long QT syndrome 3		DOID:0110646	OMIM:603830	J:186583

Genotype
MGI:6415731

ht7

• Allelic Composition: Scn5a^em1Coop/Scn5a⁺
• Genetic Background: involves: FVB/NJ

cardiovascular system

irregular heartbeat ( J:279087 )

• intracardiac pacing shows that mice are susceptible to inducible arrhythmias

abnormal impulse conducting system conduction ( J:279087 )

• optical mapping shows delays in activation and propagation of conduction, a trend of prolonged action potential duration, and decreased ventricular conduction velocity

• however, mice show no differences in ejection fraction, fractional shortening, or morphological differences, indicating that contractility is not affected

atrioventricular block ( J:279087 )

• pacing in hearts shows atrioventricular block

prolonged QRS complex duration ( J:279087 )

abnormal QT interval ( J:279087 )

• variability in corrected QT interval

abnormal sinoatrial node conduction ( J:279087 )

• in vivo intracardiac pacing on anesthetized mutants shows prolonged atrioventricular effective refractory period

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
sick sinus syndrome		DOID:13884	OMIM:163800 OMIM:608567	J:279087

Genotype
MGI:3622652

ht8

• Allelic Composition: Scn5a^tm1Pec/Scn5a⁺
• Genetic Background: involves: Swiss

mortality/aging

premature death ( J:71542 )

• 6 of 275 suddenly died around 3-6 months of age, presumably because of fatal arrhythmias

cardiovascular system

decreased heart rate ( J:71542 )

• resting heart rate is lower

irregular heartbeat ( J:71542 )

• some spontaneously develop polymorphous ventricular arrhythmias

abnormal impulse conducting system conduction ( J:71542 )

• sudden accelerations in heart rate or premature beats cause lengthening of the action potential with early afterdepolarization and trigger arrhythmias

• increase in peak and late sodium current in cardiomyoctes

• ECG recordings show abnormal and variable myocardial propagation of the electrical pulse

prolonged QT interval ( J:71542 )

• QT interval is prolonged by 55%

abnormal T wave ( J:71542 )

• T-wave is more prominent than in wild-type

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
long QT syndrome 3		DOID:0110646	OMIM:603830	J:71542