Phenotypes Associated with This Genotype

Genotype
MGI:3665480

• Allelic Composition: Wrn^tm1Led/Wrn^tm1Led
• Genetic Background: B6.129S6(BKSW)-Wrn^tm1Led

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

growth/size/body

increased susceptibility to age related obesity ( J:106446 )

• at 5 months, all homozygotes (esp. virgin females) fed a 5% fat diet show a greater increase in body weight relative to similarly fed wild-type littermates; no differences in body weight are observed up to 4 months of age

• at 5 months, mutant virgin females exhibit a 25% increase in body weight, whereas mutant males show only a 12% increase in body weight relative to wild-type mice

adipose tissue

increased abdominal adipose tissue amount ( J:106446 )

• at 9 months, homozygotes fed a 5% fat diet show an abnormal increase in visceral fat deposition relative to wild-type mice

increased inguinal fat pad weight ( J:106446 )

• at 9 months, female and male homozygotes fed a 5% fat diet show a 4-fold and 2.5-fold increase in inguinal (subcutaneous) white adipose mass, respectively, relative to wild-type counterparts

increased retroperitoneal fat pad weight ( J:106446 )

• at 9 months, female and male homozygotes fed a 5% fat diet show a similar 3-fold increase in visceral (retroperitoneal) white adipose mass relative to wild-type mice

homeostasis/metabolism

hyperglycemia ( J:106446 )

• aging homozygotes develop hyperglycemia: at 6 and 9 months, both sexes show a similar 10% and 25% increase in fasting blood glucose levels, respectively, relative to age-matched wild-type counterparts

increased circulating insulin level ( J:106446 )

• at 6 months (but not at 3 months), female and male homozygotes show a similar 2.4-fold increase in fasting serum insulin levels relative to age-matched wild-type counterparts

increased circulating hyaluronic acid level ( J:106446 )

♂ • at 4 months, male (but not female) homozygotes exhibit a 67% increase in serum hyaluronic acid levels relative to wild-type counterparts

increased circulating cholesterol level ( J:106446 )

♀ • at 6 months, virgin female homozygotes show a 44% increase in fasting total cholesterol levels relative to wild-type females; no differences are noted at 3 months

♀ • in contrast, male homozygotes show no significant differences in total cholesterol levels or HDL levels relative to wild-type males at 3 or 6 months

increased circulating triglyceride level ( J:106446 )

• at 6 months, female and male homozygotes display a 30% and 19% increase in fasting serum triglyceride levels, respectively, relative to age-matched wild-type counterparts

• however, no significant differences in serum triglyceride levels are observed at 3 or 4 months i.e. prior to the onset of age-related obesity

hyperlipidemia ( J:106446 )

insulin resistance ( J:106446 )

• at 6 months, fasting female and male homozygotes show a similar increase in insulin resistance (2.4-fold higher on the HOMA-IR index) relative to wild-type mice

cardiovascular system

aortic valve stenosis ( J:106446 )

♂ • at 12 months, male homozygotes exhibit signs of aortic stenosis, as shown by a reduced aortic diastolic pressure and an increased ventricular systolic pressure relative to wild-type males

♂ • however, aortic stenosis is compensated by an increased maximal contractility (dP/dt_max) and a reduced ejection time, indicating early signs of compensated cardiac functional hypertrophy at 12 months

cardiac interstitial fibrosis ( J:106446 )

• several aging homozygotes exhibit mild to severe cardiac interstitial fibrosis of the left ventricle on all genetic backgrounds studied, including an inbred 129/Sv, outbred (involving 129/Sv and Black Swiss) and congenic C57BL/6 background

increased left ventricle systolic pressure ( J:106446 )

♂ • at 12 months, male homozygotes exhibit an increased ventricular systolic pressure relative to wild-type males

decreased systemic arterial diastolic blood pressure ( J:106446 )

♂ • at 12 months, male homozygotes exhibit a reduced aortic diastolic pressure relative to wild-type males

cellular

cardiac interstitial fibrosis ( J:106446 )

• several aging homozygotes exhibit mild to severe cardiac interstitial fibrosis of the left ventricle on all genetic backgrounds studied, including an inbred 129/Sv, outbred (involving 129/Sv and Black Swiss) and congenic C57BL/6 background

increased cellular sensitivity to oxidative stress ( J:106446 )

• in vitro, mutant MEFs exhibit a greater increase in ROS levels after exposure to high concentrations of palmitate than wild-type MEFs

oxidative stress ( J:106446 )

• adult, but not juvenile, homozygotes exhibit severe oxidative stress followed by elevated cardiac oxidative DNA damage, all before the onset of cardiac fibrosis

• at 9 months, female homozygotes display a more severe oxidative stress, with a 2-fold higher increase in serum H₂O₂ levels and cardiac tissue reactive oxygen species relative to male homozygotes

• by 12 months, female homozygotes exhibit a 2-fold increase in cardiac oxidative DNA damage relative to wild-type females, not evident at 6 months

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Werner syndrome		DOID:5688	OMIM:277700	J:106446