Phenotypes Associated with This Genotype

Genotype
MGI:6415595

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

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

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