Phenotypes associated with this allele

• Allele Symbol: Vip^tm1Clw
• Allele Name: targeted mutation 1, Christopher S Colwell
• Allele ID: MGI:3053090
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Vip^tm1Clw/Vip^tm1Clw	B6.129S-Vip^tm1Clw	MGI:4367238
hm2	Vip^tm1Clw/Vip^tm1Clw	involves: 129S/Sv * C57BL/6	MGI:3054170
ht3	Vip^tm1Clw/Vip^+	involves: 129S/Sv * C57BL/6	MGI:3054172

Genotype
MGI:4367238

hm1

• Allelic Composition: Vip^tm1Clw/Vip^tm1Clw
• Genetic Background: B6.129S-Vip^tm1Clw

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

reproductive system

reproductive system phenotype ( J:122403 )

N • male homozygotes are fertile, despite significantly reduced serum testosterone levels

decreased seminal vesicle weight ( J:122403 )

♂ • at 4 months of age, young adult male homozygotes exhibit significantly reduced seminal vesicle weights relative to age-matched wild-type controls (0.25 +/- 0.01 g vs 0.39 +/- 0.05 g, respectively)

seminiferous tubule degeneration ( J:122403 )

♂ • at 4 months of age, male homozygotes display a significantly higher % of degenerated seminiferous tubules than wild-type males (15.23 +/- 3.22% vs 4.14 +/- 0.85%, respectively)

♂ • however, unlike aging wild-type males where 77% of all seminiferous tubules display signs of degeneration associated with reduced testis weight at 15 months, mutant males exhibit a less severe testicular aging phenotype (46.5% of degenerating tubules) with no significant loss in testis weight observed from 4 to 15 months of age

decreased testes secretion ( J:122403 )

♂ • at both 4 and 15 months of age, reduced serum testosterone levels are associated with a significant decrease in mRNA expression of two key components of testosterone biosynthesis, i.e. StAR and 3beta-HSD relative to wild-type controls; in contrast, only StAR (but not 3beta-HSD) expression is significantly reduced in wild-type males at 15 months of age

endocrine/exocrine glands

decreased seminal vesicle weight ( J:122403 )

♂ • at 4 months of age, young adult male homozygotes exhibit significantly reduced seminal vesicle weights relative to age-matched wild-type controls (0.25 +/- 0.01 g vs 0.39 +/- 0.05 g, respectively)

seminiferous tubule degeneration ( J:122403 )

♂ • at 4 months of age, male homozygotes display a significantly higher % of degenerated seminiferous tubules than wild-type males (15.23 +/- 3.22% vs 4.14 +/- 0.85%, respectively)

♂ • however, unlike aging wild-type males where 77% of all seminiferous tubules display signs of degeneration associated with reduced testis weight at 15 months, mutant males exhibit a less severe testicular aging phenotype (46.5% of degenerating tubules) with no significant loss in testis weight observed from 4 to 15 months of age

decreased testes secretion ( J:122403 )

♂ • at both 4 and 15 months of age, reduced serum testosterone levels are associated with a significant decrease in mRNA expression of two key components of testosterone biosynthesis, i.e. StAR and 3beta-HSD relative to wild-type controls; in contrast, only StAR (but not 3beta-HSD) expression is significantly reduced in wild-type males at 15 months of age

homeostasis/metabolism

decreased circulating testosterone level ( J:122403 )

• at 4 months of age, male homozygotes exhibit significantly reduced serum testosterone levels relative to age-matched wild-type controls (0.16 +/- 0.05 ng/ml vs 12.65 +/- 3.8 ng/ml, respectively)

• unlike wild-type males which show a severe (26-fold) decrease in serum testosterone levels between 4 and 15 months of age, aging mutant males maintain significantly low but constant testosterone levels that match the levels seen in aging wild-type males

decreased circulating follicle stimulating hormone level ( J:122403 )

• at 4 months of age, male homozygotes exhibit significantly reduced serum FSH levels relative to age-matched wild-type controls (58 +/- 4.94 ng/ml vs 83.44 +/- 3.08 ng/ml, respectively)

• in contrast, no significant differences in serum LH levels are observed at 4 or 15 months of age

Genotype
MGI:3054170

hm2

• Allelic Composition: Vip^tm1Clw/Vip^tm1Clw
• Genetic Background: involves: 129S/Sv * C57BL/6

behavior/neurological

shortened circadian behavior period ( J:86544 )

• in constant darkness most (20/23) mutants have a significantly shorter period

arrhythmic circadian behavior persistence ( J:86544 )

• a few (3/23) mutants become arrhythmic immediately after the onset of constant darkness and 3 of the 20 that initially display short periods become arrhythmic over time

abnormal circadian behavior phase ( J:86544 )

• at the onset of constant darkness mutants begin activity earlier than predicted from the previous light dark cycle and this onset is too early to be explained by the shorter circadian period

• mutants display 2 discrete bouts of activity when exposed to two 1 hour light pulses in a 24 hour period unlike controls which display a single bout of activity

cardiovascular system

abnormal pulmonary artery morphology ( J:132313 )

♂ • males show an enlarged, thickened pulmonary artery and smaller branches with increased muscularization and narrowed lumen

♂ • medial wall of pulmonary arteries is thicker and lumen is narrower resulting in numerous severely narrowed vessels that appear almost totally occluded

♂ • increase in proliferation of pulmonary medial smooth muscle cells

abnormal lung vasculature morphology ( J:132313 )

♂ • males exhibit pulmonary vascular remodeling

♂ • males treated with vasoactive intestinal peptide for 4 weeks show attenuation of vascular remodeling and right ventricle hypertrophy

♂ • however, renal arteries do not show any evidence of vascular thickening

heart right ventricle hypertrophy ( J:132313 )

♂ • males, but not females, exhibit moderate right ventricular hypertrophy as indicated by an increased ratio of right ventricle to left ventricle plus septum weight

♂ • males treated with vasoactive intestinal peptide for 4 weeks show attenuation of vascular remodeling and right ventricle hypertrophy

increased right ventricle systolic pressure ( J:132313 )

♂ • mean right ventricle systolic pressure is elevated in males at 40 and 48 weeks of age indicating development of moderate right ventricular hypertension

pulmonary hypertension ( J:132313 )

♂ • right ventricular systolic pressure and right ventricle to left ventricle and septum weight ratio is increased in males indicating presence of moderately severe pulmonary arterial hypertension

immune system

lung inflammation ( J:132313 )

♂ • perivascular inflammatory cell infiltrates, predominantly mononuclear infiltrates, are seen around smaller pulmonary vessels and airways of males

mortality/aging

premature death ( J:132313 )

♂ • increased mortality is seen in males, with mice starting to die at 6 months

respiratory system

abnormal lung vasculature morphology ( J:132313 )

♂ • males exhibit pulmonary vascular remodeling

♂ • males treated with vasoactive intestinal peptide for 4 weeks show attenuation of vascular remodeling and right ventricle hypertrophy

♂ • however, renal arteries do not show any evidence of vascular thickening

lung inflammation ( J:132313 )

♂ • perivascular inflammatory cell infiltrates, predominantly mononuclear infiltrates, are seen around smaller pulmonary vessels and airways of males

muscle

heart right ventricle hypertrophy ( J:132313 )

♂ • males, but not females, exhibit moderate right ventricular hypertrophy as indicated by an increased ratio of right ventricle to left ventricle plus septum weight

♂ • males treated with vasoactive intestinal peptide for 4 weeks show attenuation of vascular remodeling and right ventricle hypertrophy

growth/size/body

heart right ventricle hypertrophy ( J:132313 )

♂ • males, but not females, exhibit moderate right ventricular hypertrophy as indicated by an increased ratio of right ventricle to left ventricle plus septum weight

♂ • males treated with vasoactive intestinal peptide for 4 weeks show attenuation of vascular remodeling and right ventricle hypertrophy

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
primary pulmonary hypertension		DOID:14557	OMIM:178600 OMIM:265400 OMIM:615342 OMIM:615343 OMIM:615344	J:132313

Genotype
MGI:3054172

ht3

• Allelic Composition: Vip^tm1Clw/Vip⁺
• Genetic Background: involves: 129S/Sv * C57BL/6

behavior/neurological

abnormal circadian behavior phase ( J:86544 )

• at the onset of constant darkness heterozygous mutants begin activity slightly earlier (about 30 min) than predicted from the previous light dark cycle but not as early as homozygous mutants

• heterozygotes display a 50% reduction in the magnitude of light induced phase shifts compared to wild-type controls