Phenotypes associated with this allele

• Allele Symbol: Bub1b^tm1Jvd
• Allele Name: targeted mutation 1, Jan M A van Deursen
• Allele ID: MGI:3046580
• Summary: 9 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Bub1b^tm1Jvd/Bub1b^tm1Jvd	involves: 129S6/SvEvTac	MGI:3046582
hm2	Bub1b^tm1Jvd/Bub1b^tm1Jvd	involves: 129S6/SvEvTac * C57BL/6	MGI:6478933
hm3	Bub1b^tm1Jvd/Bub1b^tm1Jvd	involves: 129S6/SvEvTac * C57BL/6 * FVB	MGI:6791352
ht4	Bub1b^tm1Jvd/Bub1b^+	involves: 129S6/SvEvTac	MGI:3620041
ht5	Bub1b^tm1Jvd/Bub1b^tm1.1Jvd	involves: 129S6/SvEvTac	MGI:3046584
ht6	Bub1b^tm1Jvd/Bub1b^tm2.1Jvd	involves: 129S6/SvEvTac * C57BL/6	MGI:6478932
ht7	Bub1b^tm1Jvd/Bub1b^tm1.1Jvd	involves: 129S6/SvEvTac * C57BL/6	MGI:6478930
ht8	Bub1b^tm1Jvd/Bub1b^tm3.1Jvd	involves: 129S6/SvEvTac * C57BL/6	MGI:6478931
cn9	Bub1b^tm1Jvd/Bub1b^tm1Jvd Mad2l1bp^tm1.1Itl/Mad2l1bp^tm1.1Itl Speer6-ps1^Tg(Alb-cre)21Mgn/Speer6-ps1^+	involves: 129S6/SvEvTac * C57BL/6 * FVB	MGI:6791353

Genotype
MGI:3046582

hm1

• Allelic Composition: Bub1b^tm1Jvd/Bub1b^tm1Jvd
• Genetic Background: involves: 129S6/SvEvTac

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

mortality/aging

premature death ( J:91128 )

• the median life span is about 6 months

adipose tissue

decreased subcutaneous adipose tissue amount ( J:91128 )

• at 12 months of age the subcutaneous fat cell layer is significantly thinner compared to wild-type mice

decreased total body fat amount ( J:91128 )

• total body fat declines prematurely

cellular

oligozoospermia ( J:91128 )

♂ • sperm counts are about 4 time lower than in wild-type mice

abnormal cell physiology ( J:91128 )

abnormal cell cycle checkpoint function ( J:105717 )

• after nocodazole treatment the time for 50% of cells to exit prometaphase arrest is reduced to 1.1 hours compared to 7.2 hours for wild-type MEFs

abnormal mitosis ( J:105717 )

• 17% of anaphases have multiple lagging chromosomes compared to 0% in wild-type MEFs

abnormal cellular replicative senescence ( J:91128 , J:105717 )

• senescence associated markers are increased in kidneys from 5 month old mutants compared to wild-type mice (J:91128)

• the number of senescent cells is increased compared to wild-type MEFs or MEFs double heterozygous for Rae1^tm1Jvd and Bub3^tm1Jvd (J:105717)

chromosome breakage ( J:91128 )

• mild aneuploidy develops by 2 months and increases in degree and severity as the mice age

• despite the increase in aneuploidy only 7 out of 116 homozygotes developed tumo

growth/size/body

cachexia ( J:91128 )

• around 2 - 3 months mutants develop cachexia

postnatal growth retardation ( J:91128 )

• homozygotes are normal in size at birth but grow more slowly postnatally

muscle

muscular atrophy ( J:91128 )

• at 12 months muscular atrophy is seen

reproductive system

oligozoospermia ( J:91128 )

♂ • sperm counts are about 4 time lower than in wild-type mice

female infertility ( J:91128 )

♀ • females are infertile at least in part because of meiotic chromosome segregation defects

male infertility ( J:91128 )

♂ • males do not sire litters probably as a result of decreased sperm counts and abnormal meiotic chromosome segregation

♂ • sperm from males can fertilize eggs in vitro but this results in 13 times fewer 2-cell stage embryos compared to wild-type

skeleton

lordokyphosis ( J:91128 )

• around 2 - 3 months mutants develop lordokyphosis that increases in severity with age

vision/eye

cataract ( J:91128 )

• from 2 months of age, mutants develop progressive bilateral cataracts with features similar to age-related human cataracts

homeostasis/metabolism

impaired wound healing ( J:91128 )

• mutants have a decreased ability to heal wounds

integument

decreased subcutaneous adipose tissue amount ( J:91128 )

• at 12 months of age the subcutaneous fat cell layer is significantly thinner compared to wild-type mice

thin dermal layer ( J:91128 )

• at 12 months of age the dermis is significantly thinner compared to wild-type mice

Genotype
MGI:6478933

hm2

• Allelic Composition: Bub1b^tm1Jvd/Bub1b^tm1Jvd
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6

mortality/aging

premature death ( J:293084 )

• median lifespan of 196 days compared to 691 days in wild-type mice

premature aging ( J:293084 )

adipose tissue

decreased fat cell size ( J:293084 )

• average size of fat cells is reduced

lipodystrophy ( J:293084 )

• fat tissue atrophy

behavior/neurological

decreased grip strength ( J:293084 )

impaired exercise endurance ( J:293084 )

• mice show reduced work output during treadmill exercise

cardiovascular system

increased response of heart to induced stress ( J:293084 )

• mice are highly sensitive to repeated isoproterenol administration, with half dying within 5 injections, indicating a very low cardiac stress tolerance

cellular

aneuploidy ( J:293084 )

• mitotic MEFs show high rates of aneuploidy

• nearly half of MEFs exhibit whole-chromosome aneuploidy

• most aneuploidy results from chromosome gains

• aneuploidy rates in mitotic splenocytes from 5-month old mice are elevated 15%

abnormal mitosis ( J:293084 )

• MEFs exhibit impaired centrosome movement and form non-perpendicular spindles at increased rates

• MEFs show an increase in chromatin bridges

• premature chromatid separation in mitotic splenocytes from 5-month old mice is elevated

abnormal mitotic spindle assembly checkpoint ( J:293084 )

• spindle assembly checkpoint activity is severely compromised in MEFs

abnormal mitotic spindle morphology ( J:293084 )

• MEFs form non-perpendicular spindles

early cellular replicative senescence ( J:293084 )

• marker analysis indicates an increase in senescent cells in muscles and fat tissue

homeostasis/metabolism

impaired exercise endurance ( J:293084 )

• mice show reduced work output during treadmill exercise

increased response of heart to induced stress ( J:293084 )

• mice are highly sensitive to repeated isoproterenol administration, with half dying within 5 injections, indicating a very low cardiac stress tolerance

muscle

skeletal muscle fiber atrophy ( J:293084 )

skeleton

kyphosis ( J:293084 )

• mice develop kyphosis with a median onset of 175 days

vision/eye

cataract ( J:293084 )

• mice are highly sensitive to cataract formation, with a median onset of 168 days

Genotype
MGI:6791352

hm3

• Allelic Composition: Bub1b^tm1Jvd/Bub1b^tm1Jvd
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6 * FVB

growth/size/body

postnatal growth retardation ( J:234643 )

• mice fail to thrive

homeostasis/metabolism

hypoglycemia ( J:234643 )

• mice exhibit hypoglycemia in the fed state relative to wild-type controls

improved glucose tolerance ( J:234643 )

• mice exhibit increased glucose tolerance relative to wild-type controls

increased insulin sensitivity ( J:234643 )

• mice exhibit increased insulin sensitivity relative to wild-type controls

liver/biliary system

abnormal hepatocyte physiology ( J:234643 )

• freshly isolated primary hepatocytes show a more robust IR autophosphorylation and activating phosphorylation of AKT (pT308) in response to insulin, unlike hepatocytes from Mad2l1bp^tm1.1Itl/Mad2l1bp^tm1.1Itl Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺ mice

cellular

aneuploidy ( J:234643 )

• 20% (2 out of 10) live hepatocytes are aneuploid relative to none (0 of 15) wild-type hepatocytes

• aneuploidy is higher than that in hepatocytes from Mad2l1bp^tm1.1Itl/Mad2l1bp^tm1.1Itl Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺ mice

Genotype
MGI:3620041

ht4

• Allelic Composition: Bub1b^tm1Jvd/Bub1b⁺
• Genetic Background: involves: 129S6/SvEvTac

cellular

abnormal cell cycle checkpoint function ( J:105717 )

• after nocodazole treatment the time for 50% of cells to exit prometaphase arrest is reduced to 5.3 hours compared to 7.2 hours for wild-type MEFs

Genotype
MGI:3046584

ht5

• Allelic Composition: Bub1b^tm1Jvd/Bub1b^tm1.1Jvd
• Genetic Background: involves: 129S6/SvEvTac

mortality/aging

neonatal lethality, complete penetrance ( J:91128 )

• mutants die within a few hours of birth apparently from respiratory insufficiency

Genotype
MGI:6478932

ht6

• Allelic Composition: Bub1b^tm1Jvd/Bub1b^tm2.1Jvd
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6

cellular

aneuploidy ( J:293084 )

• MEFs show high rates of aneuploidy and premature chromatid separation

• nearly all MEFs exhibit whole-chromosome aneuploidy

• most aneuploidy results from chromosome gains

abnormal mitosis ( J:293084 )

• MEFs show premature chromatid separation

• MEFs exhibit higher rates of chromosome missegregation and more severely compromised error correction

• MEFs exhibit impaired centrosome movement and form non-perpendicular spindles at increased rates

abnormal mitotic spindle assembly checkpoint ( J:293084 )

• spindle assembly checkpoint activity is severely compromised in MEFs

abnormal mitotic spindle morphology ( J:293084 )

• MEFs form non-perpendicular spindles

mortality/aging

neonatal lethality, complete penetrance ( J:293084 )

• mice die shortly after birth

Genotype
MGI:6478930

ht7

• Allelic Composition: Bub1b^tm1Jvd/Bub1b^tm1.1Jvd
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6

mortality/aging

neonatal lethality, complete penetrance ( J:293084 )

• mice fail to thrive and die within 18 hours after birth

Genotype
MGI:6478931

ht8

• Allelic Composition: Bub1b^tm1Jvd/Bub1b^tm3.1Jvd
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6

mortality/aging

premature death ( J:293084 )

• median lifespan of 343 days compared to 691 days in wild-type mice

premature aging ( J:293084 )

growth/size/body

postnatal growth retardation ( J:293084 )

• mice become growth retarded during postnatal development

adipose tissue

decreased fat cell size ( J:293084 )

• average size of fat cells is reduced

lipodystrophy ( J:293084 )

• fat tissue atrophy in 8-10-month old mice

behavior/neurological

decreased grip strength ( J:293084 )

impaired exercise endurance ( J:293084 )

• mice show reduced work output during treadmill exercise

cardiovascular system

increased response of heart to induced stress ( J:293084 )

• mice are sensitive to repeated isoproterenol administration, with half dying within 18 injections, indicating lower cardiac stress tolerance than wild-type mice

cellular

aneuploidy ( J:293084 )

• MEFs show high rates of aneuploidy and premature chromatid separation

• nearly half of MEFs exhibit whole-chromosome aneuploidy

• most aneuploidy results from chromosome gains

• aneuploidy rates in mitotic splenocytes from 5-month old mice are elevated 38%

abnormal mitosis ( J:293084 )

• MEFs exhibit impaired centrosome movement and form non-perpendicular spindles at increased rates

• premature chromatid separation in mitotic splenocytes from 5-month old mice is elevated

abnormal mitotic spindle assembly checkpoint ( J:293084 )

• spindle assembly checkpoint activity is severely compromised in MEFs

abnormal mitotic spindle morphology ( J:293084 )

• MEFs form non-perpendicular spindles

early cellular replicative senescence ( J:293084 )

• marker analysis indicates an increase in senescent cells in muscles and fat tissue

homeostasis/metabolism

impaired exercise endurance ( J:293084 )

• mice show reduced work output during treadmill exercise

increased response of heart to induced stress ( J:293084 )

• mice are sensitive to repeated isoproterenol administration, with half dying within 18 injections, indicating lower cardiac stress tolerance than wild-type mice

increased incidence of tumors by chemical induction ( J:293084 )

• incidence and multiplicity of DMBA-induced lung tumors are elevated

muscle

skeletal muscle fiber atrophy ( J:293084 )

neoplasm

neoplasm ( J:293084 )

N • mice are not prone to spontaneous tumors, with only 13% of mice dying with detectable tumors

increased incidence of tumors by chemical induction ( J:293084 )

• incidence and multiplicity of DMBA-induced lung tumors are elevated

increased tumor growth/size ( J:293084 )

• the average lung tumor size is increased in DMBA-treated mice

skeleton

kyphosis ( J:293084 )

• mice develop kyphosis with a median onset of 238 days

vision/eye

cataract ( J:293084 )

• mice are highly sensitive to cataract formation, with a median onset of 161 days

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
mosaic variegated aneuploidy syndrome 1		DOID:0080141	OMIM:257300	J:293084

Genotype
MGI:6791353

cn9

• Allelic Composition: Bub1b^tm1Jvd/Bub1b^tm1Jvd; Mad2l1bp^tm1.1Itl/Mad2l1bp^tm1.1Itl; Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6 * FVB

mortality/aging

preweaning lethality, incomplete penetrance ( J:234643 )

• mice are obtained at a slightly lower than the expected number (10 versus 14.5) based on the Mendelian ratio; time of lethality is not specified

growth/size/body

decreased body weight ( J:234643 )

• mice attain ~40% of normal weight at 3 weeks of age

postnatal growth retardation ( J:234643 )

• mice appear normal at birth but fail to thrive, similar to Bub1b^tm1Jvd homozygotes

homeostasis/metabolism

hypoglycemia ( J:234643 )

• mice exhibit hypoglycemia in the fed state, similar to Bub1b^tm1Jvd homozygotes and opposite to Mad2l1bp^tm1.1Itl/Mad2l1bp^tm1.1Itl Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺ mice

improved glucose tolerance ( J:234643 )

• mice exhibit increased glucose tolerance, similar to Bub1b^tm1Jvd homozygotes and opposite to Mad2l1bp^tm1.1Itl/Mad2l1bp^tm1.1Itl Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺ mice

increased insulin sensitivity ( J:234643 )

• mice exhibit increased insulin sensitivity, similar to Bub1b^tm1Jvd homozygotes and opposite to Mad2l1bp^tm1.1Itl/Mad2l1bp^tm1.1Itl Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺ mice

liver/biliary system

abnormal hepatocyte morphology ( J:234643 )

• at 2 months of age, the cell and nuclear sizes of hepatocytes in male mice are larger than those in single knockout mice

increased hepatocyte karyomegaly ( J:234643 )

cellular

polyploidy ( J:234643 )

• mice exhibit an increased percentage of hepatocytes with 8N or greater DNA content, indicating a striking ploidy change

increased hepatocyte karyomegaly ( J:234643 )