All Phenotypes Cap2<tm1a(EUCOMM)Wtsi> MGI Mouse

• few males survive to weaning and ~70% of these survivors die suddenly between 5 and 10 weeks of age

• only ~30% of males survive to adulthood

• however, females survive about as long as wild-type mice

premature death ( J:234044 )

• ~70% of males that survive to weaning die suddenly within 12 weeks of birth while only 5.4% of females die by that age

• males are prone to sudden death without any other obvious signs of distress

postnatal lethality, incomplete penetrance ( J:234044 )

• of 115 pups born from heterozygous crosses, only 5.3% of males survive to weaning (~3 weeks) versus 16.9% of females, indicating a sex bias in survival at young ages

decreased body weight ( J:234044 )

• at P21, both sexes exhibit significantly lower body weights than heterozygous or wild-type controls

• in males, body weight is significantly reduced as early as P3

postnatal growth retardation ( J:234044 )

• both sexes show normal birth weights but grow at significantly slower rates than heterozygous or wild-type controls; this trend is more pronounced in males

• however, DEXA analysis of males revealed no differences in bone mineral content, lean muscle or fat content at 11 weeks of age

dilated heart left ventricle ( J:234044 )

• at 55 weeks of age, males show a significant increase in left ventricular internal dimension during systole (LVIDs/BW) relative to wild-type controls

• however, no significant differences in left ventricular chamber size, function and wall thickness are noted in males at 10 or 21 weeks of age, or in females at 9-109 weeks of age relative to age-matched controls

cardiac interstitial fibrosis ( J:234044 )

• fibrosis, when observed, is not present until ~12 months of age

• 1 of 3 adult males analyzed showed abundant interstitial fibrosis separating and replacing the cardiomyocytes throughout the myocardium; a more modest interstitial fibrosis was noted in a second male

• however, none of the 4 females analyzed displayed cardiac fibrosis

dilated cardiomyopathy ( J:234044 )

• surviving males develop dilated cardiomyopathy after 6 months of age

• 1 of 3 adult males analyzed showed a modest increase in right and left ventricular chamber size with abundant interstitial fibrosis

• older males exhibit signs of mild chamber dilatation

• dilated cardiomyopathy is more pronounced in males versus females

decreased heart left ventricle muscle contractility ( J:234044 )

• at 55 weeks of age, males show a significant decrease in left ventricular ejection fraction, LVEF (%), relative to wild-type controls

abnormal impulse conducting system conduction ( J:234044 )

• older mice show defects in both the suprahisian conduction system (prolonged AV Wenckebach cycle length) and the infranodal conduction system (prolonged HV-intervals)

prolonged HV interval ( J:234044 )

• older mice show a significant increase in the HV-interval relative to control mice

prolonged QRS complex duration ( J:234044 )

• both males and females exhibit increased QRS duration as they age

prolonged QT interval ( J:234044 )

• both males and females exhibit a prolonged QT interval as they age; however, the rate corrected QT-intervals are not significantly different from those in controls

• all ECG parameters are normal in males and females at ~30-weeks of age or earlier

congestive heart failure ( J:234044 )

• one male with extensive myocardial fibrosis showed increased ANP staining in the left ventricle

• a strong cardiac ankyrin repeat protein (CARP) signal was detected in 3 of 3 males, but only in 1 of 3 females

eye inflammation ( J:234044 )

• almost all males and ~50% of females are prone to eye inflammation and infections

small pupil ( J:234044 )

• males exhibit significantly decreased pupil diameters, suggesting microphthalmia

• however, no visual defects are detected by electroretinography or pupillometry

microphthalmia ( J:234044 )

• microphthalmia is seen predominantly in males

eye inflammation ( J:234044 )

• almost all males and ~50% of females are prone to eye inflammation and infections

increased susceptibility to infection ( J:234044 )

• almost all males and ~50% of females are prone to eye inflammation and infections

• eye infections typically appear at ~6 weeks of age and are more common in the right eye than the left eye

homeostasis/metabolism phenotype ( J:234044 )

N	• homozygotes display normal glucose tolerance and treadmill parameters (including VO2, VCO2, respiratory exchange ratio, and heat generated)

decreased aerobic running capacity ( J:234044 )

• when subjected to treadmill exercise tests, older males travel about half as far and do less work than wild-type controls

• in contrast, females perform as well as wild-type controls in the treadmill test

decreased grip strength ( J:234044 )

• homozygotes are weaker in grip strength assays, probably as a result of smaller size

• no ultrastructural abnormalities are noted in isolated EDL muscles

decreased aerobic running capacity ( J:234044 )

• when subjected to treadmill exercise tests, older males travel about half as far and do less work than wild-type controls

• in contrast, females perform as well as wild-type controls in the treadmill test

dilated cardiomyopathy ( J:234044 )

• surviving males develop dilated cardiomyopathy after 6 months of age

• 1 of 3 adult males analyzed showed a modest increase in right and left ventricular chamber size with abundant interstitial fibrosis

• older males exhibit signs of mild chamber dilatation

• dilated cardiomyopathy is more pronounced in males versus females

decreased heart left ventricle muscle contractility ( J:234044 )

• at 55 weeks of age, males show a significant decrease in left ventricular ejection fraction, LVEF (%), relative to wild-type controls

cardiac interstitial fibrosis ( J:234044 )

• fibrosis, when observed, is not present until ~12 months of age

• 1 of 3 adult males analyzed showed abundant interstitial fibrosis separating and replacing the cardiomyocytes throughout the myocardium; a more modest interstitial fibrosis was noted in a second male

• however, none of the 4 females analyzed displayed cardiac fibrosis

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

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

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

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

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