Phenotypes associated with this allele

• Allele Symbol: Tusc2^tm1Avi
• Allele Name: targeted mutation 1, Alla Ivanova
• Allele ID: MGI:3706236
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Tusc2^tm1Avi/Tusc2^tm1Avi	involves: 129S1/Sv	MGI:7336179
hm2	Tusc2^tm1Avi/Tusc2^tm1Avi	involves: 129S1/Sv * C57BL/6J	MGI:3707331
ht3	Tusc2^tm1Avi/Tusc2^+	involves: 129S1/Sv * C57BL/6J	MGI:3707332

Genotype
MGI:7336179

hm1

• Allelic Composition: Tusc2^tm1Avi/Tusc2^tm1Avi
• Genetic Background: involves: 129S1/Sv

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

mortality/aging

premature death ( J:309768 )

• 44% of mice died between 8 and 18 months of age; in most cases cause of death was not determined

• 2 of 54 mice (12 and 14 months of age) developed an acute autoimmune syndrome, including polyarteritis, acute renal tubular necrosis and acute glomerular thrombosis, that could be interpreted as the cause of death

premature aging ( J:309768 )

• mice developed multiple early aging signs including lordokyphosis, lack of vigor, inability to accumulate fat, reduced ability to tolerate stress, and premature death

• however, mice appeared morphologically normal up to 6 months of age

growth/size/body

decreased body weight ( J:309768 )

• in males, body weight was significantly decreased at 2, 4-5, and 11-15 months of age

• in females, body weight was significantly decreased only at 11-15 months of age, with a non-significant trend towards reduction observed at 2 and 4-5 months

abnormal susceptibility to weight gain ( J:309768 )

• males failed to gain weight after 4-5 months of age, whereas wild-type males still gained weight at 11-15 months

• females continued to gain weight even at 11-15 months, although at a slower rate than wild-type females

immune system

arteritis ( J:309768 )

• 2 of 54 mice (12 and 14 months of age) developed polyarteritis

decreased T cell proliferation ( J:309768 )

• BrdU incorporation was significantly decreased in CD4-CD8- (double negative), CD4+CD8+ (double positive), CD4 +CD8- (CD4 single positive) and CD4 -CD8+ (CD8 single positive) cells, indicating that bone marrow-derived T cell progenitors have a reduced tissue repopulation ability

decreased thymocyte number ( J:309768 )

• total thymocyte numbers were significantly decreased

increased macrophage cell number ( J:309768 )

• at 6 months of age, the proportion of CD11b+F4/80+ macrophages in spleen was significantly higher than in wild-type mice (5.5 % vs 3.7%)

• however, the proportion of splenic CD11b+CD11c+ dendritic cells was normal

increased monocyte cell number ( J:309768 )

• at 6 months of age, the proportion of splenic CD11b+F4/80+Gr1+ cells (corresponding to inflammatory monocytes) was increased by ~30%, suggesting chronic inflammation

increased susceptibility to autoimmune disorder ( J:309768 )

chronic inflammation ( J:309768 )

• at 6 months of age, mice showed an increased number of inflammatory monocytes in peripheral blood and spleen

hematopoietic system

decreased T cell proliferation ( J:309768 )

• BrdU incorporation was significantly decreased in CD4-CD8- (double negative), CD4+CD8+ (double positive), CD4 +CD8- (CD4 single positive) and CD4 -CD8+ (CD8 single positive) cells, indicating that bone marrow-derived T cell progenitors have a reduced tissue repopulation ability

decreased thymocyte number ( J:309768 )

• total thymocyte numbers were significantly decreased

increased macrophage cell number ( J:309768 )

• at 6 months of age, the proportion of CD11b+F4/80+ macrophages in spleen was significantly higher than in wild-type mice (5.5 % vs 3.7%)

• however, the proportion of splenic CD11b+CD11c+ dendritic cells was normal

increased monocyte cell number ( J:309768 )

• at 6 months of age, the proportion of splenic CD11b+F4/80+Gr1+ cells (corresponding to inflammatory monocytes) was increased by ~30%, suggesting chronic inflammation

increased myeloid cell number ( J:309768 )

• at 6 months of age, the number of Gr1 + myeloid cells in peripheral blood was significantly higher than in wild-type mice (37% vs 24%)

renal/urinary system

renal tubular necrosis ( J:309768 )

• 2 of 54 mice (12 and 14 months of age) developed acute renal tubular necrosis

skeleton

lordokyphosis ( J:309768 )

• 50% of mice showed signs of lordokyphosis by 9-12 months of age, not observed in age-matched wild-type mice

• ~80% of developed lordokyphosis by 18 months

cellular

oligozoospermia ( J:309768 )

♂ • cauda epididymal sperm count was significantly reduced at 11-12 months, but not at 6 months of age, indicating a premature decrease in sperm count

asthenozoospermia ( J:309768 )

♂ • sperm motility was significantly reduced at 11-12 months of age

decreased T cell proliferation ( J:309768 )

• BrdU incorporation was significantly decreased in CD4-CD8- (double negative), CD4+CD8+ (double positive), CD4 +CD8- (CD4 single positive) and CD4 -CD8+ (CD8 single positive) cells, indicating that bone marrow-derived T cell progenitors have a reduced tissue repopulation ability

abnormal oxidative phosphorylation ( J:309768 )

• both primary mouse embryonic fibroblasts (MEFs) and immortalized kidney epithelial cells (iKECs) showed significantly lower maximal respiration (MR) and reserve respiratory capacity (RRC) than wild-type cells, indicating a reduced ability of cells to produce additional ATP in response to increased energy demands

behavior/neurological

abnormal response to novelty ( J:309768 )

♀ • mice of pup-bearing age were extremely sensitive to stress-inducing environments, such as increased traffic and prolonged light exposure after installation of a new hood close to the mating cages

♀ • under poor environmental conditions, both frequency of pregnancies and maternal behavior were decreased, indicating reduced ability to tolerate stress

♀ • however, normal breeding and maternal behavior were restored shortly after cages were placed in the quiet and darker corner of the room and supplemented with shredded paper and igloos for nesting

weakness ( J:309768 )

• mice exhibit an absence of vigor by 9-12 months of age

abnormal nursing ( J:309768 )

♀ • mothers failed to feed their newborns under stress-inducing environmental conditions; all pups from occasional litters born during this time died due to negligence

reproductive system

oligozoospermia ( J:309768 )

♂ • cauda epididymal sperm count was significantly reduced at 11-12 months, but not at 6 months of age, indicating a premature decrease in sperm count

asthenozoospermia ( J:309768 )

♂ • sperm motility was significantly reduced at 11-12 months of age

enlarged seminal vesicle ( J:309768 )

♂ • at 16-18 months of age, some males showed enlarged seminal vesicles, an infrequent aging lesion that occurs spontaneously in wild-type males at 24 months or later

♂ • premature enlargement of seminal vesicles included asymmetrical enlargement, symmetrical enlargement, and enlargement with discoloration

small testis ( J:309768 )

♂ • at 11-12 months of age, ~10% of males showed a symmetrical or unilateral reduction in testis size, not observed in age-matched wild-type males

testis degeneration ( J:309768 )

♂ • occasionally, adult males showed unilateral or bilateral testes degeneration with marked mineralization in some cases

abnormal cauda epididymis morphology ( J:309768 )

♂ • some aging males showed marked mineralization in the cauda epididymis

small cauda epididymis ( J:309768 )

♂ • at 11-12 months of age, ~10% of males showed a symmetrical or unilateral reduction in cauda size, not observed in age-matched wild-type males

abnormal pregnancy ( J:309768 )

♀ • frequency of pregnancies was severely reduced under stress-inducing environmental conditions

cardiovascular system

arteritis ( J:309768 )

• 2 of 54 mice (12 and 14 months of age) developed polyarteritis

endocrine/exocrine glands

decreased thymocyte number ( J:309768 )

• total thymocyte numbers were significantly decreased

enlarged seminal vesicle ( J:309768 )

♂ • at 16-18 months of age, some males showed enlarged seminal vesicles, an infrequent aging lesion that occurs spontaneously in wild-type males at 24 months or later

♂ • premature enlargement of seminal vesicles included asymmetrical enlargement, symmetrical enlargement, and enlargement with discoloration

small testis ( J:309768 )

♂ • at 11-12 months of age, ~10% of males showed a symmetrical or unilateral reduction in testis size, not observed in age-matched wild-type males

testis degeneration ( J:309768 )

♂ • occasionally, adult males showed unilateral or bilateral testes degeneration with marked mineralization in some cases

homeostasis/metabolism

abnormal glomerular capillary thrombosis ( J:309768 )

• 2 of 54 mice (12 and 14 months of age) developed acute glomerular thrombosis

abnormal calcium ion homeostasis ( J:309768 )

• primary MEFs and immortalized kidney epithelial cells (iKECs) showed significantly altered dynamics of the cellular calcium response

increased physiological sensitivity to xenobiotic ( J:309768 )

• mice showed increased sensitivity to the anesthetics avertin, pentobarbital and chloral hydrate than wild-type mice

integument

abnormal hair growth ( J:309768 )

• in a hair-growth assay, none of five 12-month-old mice showed hair regrowth at 10 days and all of them failed to close the shaved area at 3 months post-shaving

Genotype
MGI:3707331

hm2

• Allelic Composition: Tusc2^tm1Avi/Tusc2^tm1Avi
• Genetic Background: involves: 129S1/Sv * C57BL/6J

mortality/aging

premature death ( J:119985 )

• 11% of mice die between 2 and 14 months of age; some show signs of systemic infection, whereas others show necrotizing arteritis in multiple organs, severe glomerulonephrits, severe nephropathy, and anemia

• some animals develop tumors and die prematurely

growth/size/body

decreased body weight ( J:119985 )

• homozygous mice show an ~20% reduction in body weight compared to wild-type by 6 months of age

cardiovascular system

vascular inflammation ( J:119985 )

• some mice show a vasculitis syndrome

arteritis ( J:119985 )

• 20% of mice dying before or sacrificed at 2 years of age develop arteritis in single or multiple organs

• arteritis is found in large vessels and small arteries, veins and capillaries

• multiple organs like the heart, kidney, liver, lung pancreas, spleen, lymph nodes, thyroid, gall bladder, tongue, spinal cord muscles, and omentum show arteritis; some mice develop necrotizing arteritis in pancreas, liver, spleen, small intestine, ovary, uterus, urethra, and spinal cord

• some arteritic lesions show infiltration of entire vessel with fibrinoid necrosis

hematopoietic system

abnormal NK cell differentiation ( J:119985 )

• a decreased percentage of NK cells expressing Ly49G is seen in the liver (57%) and spleen (35%) indicating maturation is defective, with a blockade at the immature CD94^bright stage

decreased erythrocyte cell number ( J:119985 )

• 3 mice showing arteritis and/or glomerulonephritis had low red blood cell counts

decreased NK cell number ( J:119985 )

• at 4 weeks of age, a 45% decrease in total number of NK cells compared to controls is observed; in spleen, decrease is ~56%, while in bone marrow it is ~45%; there is no difference in the liver

increased leukocyte cell number ( J:119985 )

• 2 mice showing arteritis and/or glomerulonephritis had dramatically elevated white blood cell counts

immune system

arteritis ( J:119985 )

• 20% of mice dying before or sacrificed at 2 years of age develop arteritis in single or multiple organs

• arteritis is found in large vessels and small arteries, veins and capillaries

• multiple organs like the heart, kidney, liver, lung pancreas, spleen, lymph nodes, thyroid, gall bladder, tongue, spinal cord muscles, and omentum show arteritis; some mice develop necrotizing arteritis in pancreas, liver, spleen, small intestine, ovary, uterus, urethra, and spinal cord

• some arteritic lesions show infiltration of entire vessel with fibrinoid necrosis

abnormal NK cell differentiation ( J:119985 )

• a decreased percentage of NK cells expressing Ly49G is seen in the liver (57%) and spleen (35%) indicating maturation is defective, with a blockade at the immature CD94^bright stage

decreased NK cell number ( J:119985 )

• at 4 weeks of age, a 45% decrease in total number of NK cells compared to controls is observed; in spleen, decrease is ~56%, while in bone marrow it is ~45%; there is no difference in the liver

increased leukocyte cell number ( J:119985 )

• 2 mice showing arteritis and/or glomerulonephritis had dramatically elevated white blood cell counts

decreased interleukin-15 secretion ( J:119985 )

• Il15 production is decreased compared to wild-type

increased susceptibility to autoimmune disorder ( J:119985 )

• some mice which died prematurely showed arteritis, severe kidney abnormalities and anemia which are hallmarks of autoimmune disorder whereas wild-type mice did not display any of these

increased anti-nuclear antigen antibody level ( J:119985 )

• circulating autoreactive nuclear antibodies are detected

glomerulonephritis ( J:119985 )

• severe glomerulonephritis sometimes associated with extensive tubular cast formation

neoplasm

abnormal tumor incidence ( J:119985 )

• no distinct tumor pattern is observed in organs outside the hematopoietic system

increased hemangioma incidence ( J:119985 )

• ~32% of mice develop mixed hemangioma/hemangiosarcoma or either independently compared to ~4% in wild-type; females are most susceptible to these tumor types

increased lymphoma incidence ( J:119985 )

• 1 mouse developed lymphoma at 7 months of age

increased squamous cell carcinoma incidence ( J:119985 )

• one mouse developed an invasive squamous cell skin carcinoma at 13 months of age

increased hemangiosarcoma incidence ( J:119985 )

renal/urinary system

abnormal renal glomerulus morphology ( J:119985 )

• glomerular lesions often include membranoproliferative changes, wire-loop-like subendothelial deposits, and intracapillary thrombi that often obstruct the capillary lumen

glomerulonephritis ( J:119985 )

• severe glomerulonephritis sometimes associated with extensive tubular cast formation

renal cast ( J:119985 )

• extensive tubular cast formation

homeostasis/metabolism

abnormal glomerular capillary thrombosis ( J:119985 )

adipose tissue

adipose tissue necrosis ( J:119985 )

• one mice presenting a vasculitis syndrome developed fat necrosis

Genotype
MGI:3707332

ht3

• Allelic Composition: Tusc2^tm1Avi/Tusc2⁺
• Genetic Background: involves: 129S1/Sv * C57BL/6J

mortality/aging

premature death ( J:119985 )

• 11% of mice die between 2 and 14 months of age; some show signs of systemic infection, whereas others show necrotizing arteritis in multiple organs, severe glomerulonephrits, severe nephropathy, and anemia

• some animals develop tumors and die prematurely

cardiovascular system

vascular inflammation ( J:119985 )

• some mice show a vasculitis syndrome

arteritis ( J:119985 )

• 20% of mice dying before or sacrificed at 2 years of age develop arteritis in single or multiple organs

• arteritis is found in large vessels and small arteries, veins and capillaries

• multiple organs like the heart, kidney, liver, lung pancreas, spleen, lymph nodes, thyroid, gall bladder, tongue, spinal cord muscles, and omentum show arteritis; some mice develop necrotizing arteritis in pancreas, liver, spleen, small intestine, ovary, uterus, urethra, and spinal cord

• some arteritic lesions show infiltration of entire vessel with fibrinoid necrosis

hematopoietic system

decreased erythrocyte cell number ( J:119985 )

• 2 mice showing arteritis and/or glomerulonephritis had low red blood cell counts

immune system

arteritis ( J:119985 )

• 20% of mice dying before or sacrificed at 2 years of age develop arteritis in single or multiple organs

• arteritis is found in large vessels and small arteries, veins and capillaries

• multiple organs like the heart, kidney, liver, lung pancreas, spleen, lymph nodes, thyroid, gall bladder, tongue, spinal cord muscles, and omentum show arteritis; some mice develop necrotizing arteritis in pancreas, liver, spleen, small intestine, ovary, uterus, urethra, and spinal cord

• some arteritic lesions show infiltration of entire vessel with fibrinoid necrosis

increased susceptibility to autoimmune disorder ( J:119985 )

• some mice which died prematurely showed arteritis, severe kidney abnormalities and anemia which are hallmarks of autoimmune disorder whereas wild-type mice did not display any of these

increased anti-nuclear antigen antibody level ( J:119985 )

• circulating autoreactive nuclear antibodies are detected

glomerulonephritis ( J:119985 )

• severe glomerulonephritis sometimes associated with extensive tubular cast formation

renal/urinary system

abnormal renal glomerulus morphology ( J:119985 )

• glomerular lesions often include membranoproliferative changes, wire-loop-like subendothelial deposits, and intracapillary thrombi that often obstruct the capillary lumen

glomerulonephritis ( J:119985 )

• severe glomerulonephritis sometimes associated with extensive tubular cast formation

renal cast ( J:119985 )

• severe glomerulonephritis sometimes associated with extensive tubular cast formation

neoplasm

abnormal tumor incidence ( J:119985 )

• no distinct tumor pattern is observed in organs outside the hematopoietic system

increased hemangioma incidence ( J:119985 )

• ~23% of mice develop mixed hemangioma/hemangiosarcoma or either independently compared to ~4% in wild-type

increased leukemia incidence ( J:119985 )

• one female presented an erythroleukemia

increased lymphoma incidence ( J:119985 )

• 2 mice develop types of lymphomas at 8 and 12 months of age, respectively compared to 0 tumors in wild-type mice

increased hemangiosarcoma incidence ( J:119985 )

homeostasis/metabolism

abnormal glomerular capillary thrombosis ( J:119985 )

adipose tissue

adipose tissue necrosis ( J:119985 )

• one mouse presenting with vasculitis syndrome developed fat necrosis