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Allele Symbol Allele Name Allele ID |
Tsc1tm1Djk targeted mutation 1, David J Kwiatkowski MGI:2656240 |
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| Summary |
25 genotypes
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• about a 40% increase in liver mass following adenoviral cre retro-orbital injection
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• increase in hepatocyte size following adenoviral cre retro-orbital injection
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• decrease in liver protein content following adenoviral cre retro-orbital injection
• in cre injected mice, the liver is largely refractory to fast induced shrinkage
• cre injected mice are unable to generate ketones when given sodium octanoate
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• markedly lower serum ketones in young fasted cre injected mice but not in aged fasted cre injected mice
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• in fasted cre injected mice
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• in fasted cre injected mice
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• about a 40% increase in liver mass following adenoviral cre retro-orbital injection
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• mice injected with adenovirus expressing Cre (AdCre) into the bladder at 2-3 months of age start to die at 6 months of age and have a median survival of 10.2 months
• mice injected with AdCre intraperitoneally exhibit a median survival of 8.5 months and 89% of mice die during one year of follow-up after AdCre injection
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• 73% of mice injected with AdCre into the bladder exhibit mesothelioma
• 85% of mice injected with AdCre intraperitoneally develop mesothelioma
• malignant tumor, similar to epithelioid mesothelioma, is seen on all peritoneal surfaces, including the bladder, kidney, spleen, liver and intestines, without evidence of a primary site, in mice injected with AdCre
• mice that develop mesothelioma following AdCre injection and are treated with rapamycin for 5 weeks show inhibition of tumor growth
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• mice injected with AdCre into the bladder often exhibit hemorrhagic ascites
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| malignant mesothelioma | DOID:1790 |
OMIM:156240 |
J:212578 | |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
 |
• mice exhibit similar acquisition learning of a submerged escape-platform location compared to controls, however when the escape platform location is reversed, mutants show impaired learning of the new platform location
• rapamycin treatment prevents the reversal learning impairment
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• mice show reduced investigation of social odors compared with controls, suggesting impaired discrimination of social olfactory cues
• however, mice show normal investigation of non-social olfactory cues
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• increase in self-grooming rates
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• mutants show initial signs of ataxia at 7-8 weeks of age which progresses with age
• mice show decreased stride length and increased stride width at 4 months of age
• rapamycin treated mutants do not show ataxic gait
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• mutants show impaired motor learning on the accelerating rotarod test before ataxia onset
• treatment with rapamycin prevents the motor phenotypes
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• mice show impaired male-female social interactions, with reductions in the time that mice spend interacting compared to controls
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• in a 3-chambered assay of social approach and preference for social novelty, mice show social impairments, showing no differences between the time spend in the chamber or in interaction with the novel mouse versus the novel object
• in a social novelty paradigm, mice show no preference for social novelty
• treatment with rapamycin results in normal social behavior
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• P5-P12 pups show increased vocalizations
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• cerebellar Purkinje cell layer is abnormal with increased soma area and reduced Purkinje cell numbers
• treatment with rapamycin starting at P7 prevents the Purkinje cell defects
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• Purkinje cell soma area is increased at 4 weeks of age
• markers for endoplasmic reticulum and oxidative stress are elevated indicating elevated neuronal stress of Purkinje cells
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• Purkinje cells display abnormal axonal projections with numerous protrusions and abnormal collateralization
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• increase in spine density on Purkinje cell dendrites
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• decrease in Purkinje cell numbers are first seen at 2 months of age, with a further reduction at 4 months
• an increase in Purkinje cell apoptosis is seen at 7-8 weeks of age
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• Purkinje cell excitability is reduced, with Purkinje cells showing lower, graded spontaneous spiking rate, and current injection evokes fewer action potentials in Purkinje cells
• injection of small hyperpolarizing currents results in smaller voltage changes in Purkinje cells, indicating a decrease in the effective input resistance
• despite receiving normal functioning synaptic inputs, the output of the cerebellar cortex is reduced, both tonically and in response to incoming excitatory drive
• however, alterations in synaptic transmission are not apparent in mutants
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| autism spectrum disorder | DOID:0060041 | J:186699 | ||
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• mice show reduced investigation of social odors compared with controls, suggesting impaired discrimination of social olfactory cues
• however, mice show normal investigation of non-social olfactory cues
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• increase in self-grooming rates
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• mice show impaired male-female social interactions, with reductions in the time that mice spend interacting compared to controls
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• in a 3-chambered assay of social approach and preference for social novelty, mice exhibit social impairments, showing no differences between the time spend in the chamber or in interaction with the novel mouse versus the novel object unlike controls
• in a social novelty paradigm, mice show no preference for social novelty
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• P5-P12 pups show increased vocalizations
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• increase in spine density on Purkinje cell dendrites
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• Purkinje cell excitability is reduced, with Purkinje cells showing lower, graded spontaneous spiking rate, and current injection evokes fewer action potentials in Purkinje cells
• injection of small hyperpolarizing currents results in smaller voltage changes in Purkinje cells, indicating a decrease in the effective input resistance
• despite receiving normal functioning synaptic inputs, the output of the cerebellar cortex is reduced, both tonically and in response to incoming excitatory drive
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• midian survival was 6 months
• none survived past 8 months
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• pulmonary congestion
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• focal appearance of enlarged cardiac myocytes with apparent vacuoles
• scattered intramural foci of enlarged cells with excess glycogen revealed by histologic studies at 2 and 5 month of age
• there was no evidence of proliferative cardiac tumors
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• with heart enlargement and pulmonary congestion
• a significant increase in LV end-diastolic diameter and LV end-systolic diameter, and a reduction in fractional shortening in 2- to 3-month-old mutant mice by echocardiographic analysis
• increase in heart weight, heart/body weight ratio and heart weight/tibial length ratio
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• a significant increase in LV end-diastolic diameter and LV end-systolic diameter, and a reduction in fractional shortening in 2- to 3-month-old mutant mice by echocardiographic analysis
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• focal appearance of enlarged cardiac myocytes with apparent vacuoles
• scattered intramural foci of enlarged cells with excess glycogen revealed by histologic studies at 2 and 5 month of age
• there was no evidence of proliferative cardiac tumors
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• with heart enlargement and pulmonary congestion
• a significant increase in LV end-diastolic diameter and LV end-systolic diameter, and a reduction in fractional shortening in 2- to 3-month-old mutant mice by echocardiographic analysis
• increase in heart weight, heart/body weight ratio and heart weight/tibial length ratio
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• a significant increase in LV end-diastolic diameter and LV end-systolic diameter, and a reduction in fractional shortening in 2- to 3-month-old mutant mice by echocardiographic analysis
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• the presence of thrombus in the left atrium in some
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• pulmonary congestion
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| tuberous sclerosis | DOID:13515 |
OMIM:PS191100 |
J:96138 | |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Brains of Tsc1tm1Djk/Tsc1tm1Djk Gt(ROSA)26Sortm1Sho/Gt(ROSA)26Sor+ mice injected with an adenovirus expressing cre recombinase show ventricular region abnormalities
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• mice injected with a high dose of adenovirus expressing cre (AAVrh8-CBA-Cre) into each cerebral lateral ventricle on the day of birth exhibit a median survival of 38 days
• mice injected with a low dose of adenovirus expressing cre (AAVrh8-CBA-Cre) into each cerebral lateral ventricle on the day of birth exhibit a median survival of 180 days
• mice injected with a high dose of a different adenovirus expressing cre (AAV1-CBA-Cre) into each cerebral lateral ventricle on the day of birth exhibit a median survival of 66.5 days
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• mice injected with the AAV1-CBA-Cre adenovirus exhibit signs of distress at 1-5 months of age, including hunched back, dehydration, and weight loss
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• brains exhibit a smoother surface in mice injected with the AAV1-CBA-Cre adenovirus
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• severe hydrocephalus in 2 of 10 and mild hydrocephalus in 6 of 10 mice injected with AAV1-CBA-Cre
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• brains appear enlarged and swollen in 30 day old mice injected with the high dose of adenovirus (AAVrh8-CBA-Cre or AAV1-CBA-Cre) expressing cre
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• ventricular volume at P30 is about 4 times larger in mice injected with the AAV1-CBA-Cre adenovirus, while the brain tissue volume is about 6% larger
• 3 of 4 AAV1-CBA-Cre injected mice show nodules and thickening of the ventricular lining
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• massively enlarged lateral ventricles in mice injected with AAV1-CBA-Cre, resulting from a constriction between the 3rd and lateral ventricles
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• mice injected with AAV1-CBA-Cre develop hypertrophy of the subependymal layer, with expansion of the normal one cell thick layer into a convoluted layer with projections and isolated nodules
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• almost 2-fold increase in neuronal diameter near the periventricular area of 30 day old mice injected with the high dose of adenovirus expressing cre (AAVrh8-CBA-Cre or AAV1-CBA-Cre)
• some phospho-S6-positive Purkinje cells in the cerebellum and neurons in the caudate are enlarged in mice injected with AAV1-CBA-Cre
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• mice injected with the high dose of adenovirus expressing cre (AAVrh8-CBA-Cre or AAV1-CBA-Cre) develop a hunched back
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| tuberous sclerosis | DOID:13515 |
OMIM:PS191100 |
J:221022 | |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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N |
• males are fertile and able to sire multiple litters at a normal frequency through 12 weeks of age
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• many ovulated oocytes are not competent, suggesting that oocyte maturation is disrupted
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• after normal ovulation, 83% of oocytes collected from the oviducts during estrus are atretic (degenerated) relative to only 4% in control females
• after superovulation, the number of atretic oocytes is 7-fold higher than that in control females
• however, the number of healthy oocytes is not significantly altered
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• by 5 months of age, 100% of males show complete or partial loss of germ cells and tubules with only Sertoli cells
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• Dietrick's staining showed significantly fewer primordial follicles at 12 weeks of age; immunofluorescence staining with oocyte-specific marker MVH confirmed that fewer primordial follicles are present in the cortex
• decrease in primordial follicles is more severe at 24 weeks of age
• however, number of total follicles and primordial follicles is normal at 6 weeks of age
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• number of atretic follicles is normal at 6 weeks but significantly increased at 12 weeks of age
• a non-significant trend towards a higher atretic follicle number is noted at 24 weeks
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• ovarian folliculogenesis is disrupted
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• testicular junction integrity is compromised
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• adult Sertoli cells show disruption of cell cycle quiescence and thus increased proliferation in mice older than 4 months of age
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• by 5 months of age, 100% of males show complete or partial loss of germ cells and tubules with only Sertoli cells
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• 12 week old, but not 4 week old, testes show vacuolization of seminiferous epithelium
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• Sertoli cells show disruption of the spoke-like pattern of microtubules and loss of apical extensions, and disruption of actin filament arrangement, indicating disruption of polarity
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• small testis in adult males
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• decreased testis weight in adult males
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• at estrus, ovarian mRNA levels of Muc1 (mucin 1, transmembrane) are reduced by 50% whereas mRNA levels of Hif1a (hypoxia inducible factor 1, alpha subunit) are increased by 50% relative to control ovaries
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• females show premature ovarian insufficiency, possibly related to increased time spent in estrus
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• however, ciliated and secretory epithelial cells of the distal oviduct appear intact
• secretory epithelial cell disorganization and dysplasia is observed in the proximal portion of the oviduct, occluding the lumen
• occlusion of the proximal oviduct is likely to inhibit proper transit of embryos through the oviduct, contributing to female infertility
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• at E3.5 after natural mating, bilateral swelling of the ampullas resembling hydrosalpinges is observed in all females due to occlusion of the proximal oviduct, whereas no swelling is seen in controls females
• upon puncture, blastocysts and many degenerated bodies (~75%) are released from the swollen ampulla
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• endometrial epithelial cells continue to proliferate in E4.5 uteri, unlike in control uteri
• however, no evidence of endometrial cancer is observed
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• females exhibit significant myometrial hyperplasia mice as they age
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• immature round germ cells are seen in the epididymides whereas only mature elongated germ cells are seen in controls
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• duration of diestrus is shortened
• however, serum 17beta-estradiol (E2) progesterone (P4) levels at diestrus are normal
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• duration of the estrous stage is prolonged
• however, serum 17beta-estradiol (E2) progesterone (P4) levels at estrus are normal
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• at E4.5 after natural mating, no implantation sites are detected, unlike in controls females
• endometrial epithelial cells continue to proliferate and Muc1 mRNA expression remains elevated in E4.5 uteri (with no changes in progesterone receptor mRNA levels), suggesting that Muc1 continued expression may contribute to failure of implantation
• transfer of E3.5 wild-type embryos into uteri of pseudopregnant mutant female mice fails, with no evidence of embryo implantation sites 4-6 days after transfer
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• females mated with control males of known fertility fail to produce any offspring over a 5-month breeding period
• however, seminal plugs are observed suggesting normal female mating behavior
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• many ovulated oocytes are not competent, suggesting that oocyte maturation is disrupted
|
|
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• after normal ovulation, 83% of oocytes collected from the oviducts during estrus are atretic (degenerated) relative to only 4% in control females
• after superovulation, the number of atretic oocytes is 7-fold higher than that in control females
• however, the number of healthy oocytes is not significantly altered
|
|
|
• by 5 months of age, 100% of males show complete or partial loss of germ cells and tubules with only Sertoli cells
|
|
|
• adult Sertoli cells show disruption of cell cycle quiescence and thus increased proliferation in mice older than 4 months of age
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• females show premature ovarian insufficiency, possibly related to increased time spent in estrus
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• after natural mating, more E2.5 embryos are detected in the oviducts but 75% of them are degenerated embryos
• at E3.5 after natural mating, no blastocysts are detected in the uteri after flushing, unlike in control females
• however, the absolute number of good-quality embryos found in the ampullas is normal at both E2.5 and E3.5, suggesting that good-quality oocytes can develop into blastocysts
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• Dietrick's staining showed significantly fewer primordial follicles at 12 weeks of age; immunofluorescence staining with oocyte-specific marker MVH confirmed that fewer primordial follicles are present in the cortex
• decrease in primordial follicles is more severe at 24 weeks of age
• however, number of total follicles and primordial follicles is normal at 6 weeks of age
|
|
|
• number of atretic follicles is normal at 6 weeks but significantly increased at 12 weeks of age
• a non-significant trend towards a higher atretic follicle number is noted at 24 weeks
|
|
|
• ovarian folliculogenesis is disrupted
|
|
|
• testicular junction integrity is compromised
|
|
|
• adult Sertoli cells show disruption of cell cycle quiescence and thus increased proliferation in mice older than 4 months of age
|
|
|
• by 5 months of age, 100% of males show complete or partial loss of germ cells and tubules with only Sertoli cells
|
|
|
• 12 week old, but not 4 week old, testes show vacuolization of seminiferous epithelium
|
|
|
• Sertoli cells show disruption of the spoke-like pattern of microtubules and loss of apical extensions, and disruption of actin filament arrangement, indicating disruption of polarity
|
|
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• small testis in adult males
|
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• decreased testis weight in adult males
|
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• at estrus, ovarian mRNA levels of Muc1 (mucin 1, transmembrane) are reduced by 50% whereas mRNA levels of Hif1a (hypoxia inducible factor 1, alpha subunit) are increased by 50% relative to control ovaries
|
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• females show premature ovarian insufficiency, possibly related to increased time spent in estrus
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N |
• no evidence of endometrial or ovarian cancer is observed
(J:181774)
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N |
• testicular tumors are not observed up to 10 months of age
(J:187754)
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• following exposure to doxycycline in utero, mice die 3 to 4 weeks after birth with giant polycystic kidneys
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• following exposure to doxycycline in utero, newborn mice exhibit fulminant cysts and giant polycystic kidneys form by 3 to 4 weeks of age
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• following exposure to doxycycline in utero, new born mice exhibit hyperplasia of the proximal and distal tubules and collecting duct epithelium
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• following exposure to doxycycline in utero, newborn mice exhibit fulminant cysts and giant polycystic kidneys form by 3 to 4 weeks of age
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| autosomal recessive polycystic kidney disease | DOID:0110861 |
OMIM:263200 |
J:140925 | |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• mice die within the first postnatal week
• however, treatment with rapamycin improves phenotype
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• mice clasp hindlimbs unlike wild-type mice
• however, treatment with rapamycin improves phenotype
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• mice are severely hypoactive compared to wild-type mice
• however, treatment with rapamycin improves phenotype
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• brain weight is 2.5-fold greater than in wild-type mice
• however, treatment with rapamycin improves phenotype
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• mice administered tamoxifen from P1 to P2 show an approximate 2-fold increase in the number of mitotic cells per field in the retina
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• mice administered tamoxifen from P1 to P3 exhibit increased vascular branching and endothelial cell coverage in P5 retinas
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• at 3-4 months after tamoxifen administration, nearly 50% of mice develop liver tumors and by 6-8 months after tamoxifen, almost all mice develop liver tumors
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• small metastatic nodules are seen in the lymphatic vessels near primary tumors of tamoxifen treated mice
• macrometastases are commonly present in lymph nodes and seen in distant sites such as the sternal musculature at lower frequencies
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• mice administered tamoxifen at 2 months of age develop endothelial proliferative lesions from vascular malformations that lead to vascular tumors (angiosarcoma/lymphangiosarcoma); cutaneous tumors in tails and paws and liver tumors develop at 3 months or more after tamoxifen treatment
• cutaneous tumors are also seen on the lips and legs at later time points
• at 3-4 months and 6-8 months after tamoxifen administration, about 30% and 80% of mice develop cutaneous tumors, respectively
• poorly differentiated cutaneous lymphangiosarcomas are highly invasive
• mice treated with rapamycin starting 1 week after tamoxifen administration, do not develop cutaneous or liver tumors
• mice treated with rapamycin after the formation of tumors at 3 months after tamoxifen administration show halted tumor progression and even reduced tumor size and improved survival
• mice treated with axitinib after the formation of tumors at 5 months after tamoxifen show decreased proliferation of tumors, however tumors do not shrink and the number of apoptotic cells remains similar to untreated mice
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• cutaneous tumors are seen on paws and legs of tamoxifen treated mice
• poorly differentiated cutaneous lymphangiosarcomas on the extremities show local invasion into bone
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• mice administered tamoxifen from P1 to P3 exhibit increased vascular branching and endothelial cell coverage in P5 retinas
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• mice administered tamoxifen from P1 to P3 exhibit increased vascular branching and endothelial cell coverage in P5 retinas
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• 1 month after tamoxifen administration, some mice develop edema, with swelling in paws and tails
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• at 3-4 months after tamoxifen administration, nearly 50% of mice develop liver tumors and by 6-8 months after tamoxifen, almost all mice develop liver tumors
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• normal susceptibility to ischemic brain injury after applying middle cerebral artery occlusion (MCAO)
|
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|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• clinical features, survival, and brain pathology are stated to be identical to that of Tsc1tm1DjkTsc1tm1.1DjkTg(Syn1-cre)671Jxm conditional mutants; however no data are presented
|
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• premature death
• die by 18 weeks
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• poor weight gain
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| N |
• low frequency glutamatergic synaptic transmission is normal in mutants
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• hippocampal slices exposed to aCSF containing 6.5 mM potassium exhibited spontaneous interictal epileptiform bursting at a higher frequency than control slices
(J:116872)
• occasional seizures at 4 weeks of age
(J:167241)
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• at 1 and 3 months, higher numbers of apoptotic cells are detected in neocortex, CA1 and CA3 pyramidal cell layers and dentate gyrus (granular and subgranular layers) compared to control brains
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• gross, generalized megencephaly
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• increased brain weight starting at 3 weeks of age
• become progressively more obvious with time
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• progressive neuronal disorganization in hippocampus with a dispersion of the pyramidal cell layer
• greater CA1 pyramidal cell layer width in hippocampus
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• increased astrocyte number in neocortex beyond 3 weeks of age
• increased astrocyte number in hippocampus beyond 1 weeks of age
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• glutamate transport by astrocytes is impaired, resulting in elevated extracellular fluid glutamate (ECF) concentrations in the hippocampus at 4 weeks of age
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• barium-sensitive conductances are lower in Tsc1-null neurons relative to wild-type
• barium-sensitive inwardly rectifying potassium currents in cultured astrocytes show reduced amplitudes at all hyper- and depolarizing voltages used for stimulation compared with wild-type neurons; similarly currents in glia in tissue slices are reduced in response to voltage steps
• astrocytes have significantly lower peak barium-sensitive current in response to neuronal activation than controls
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• LTP induced by tetanic stimulation is significantly decreased compared to controls
• this effect is partially reversed by partial blockade of NMDA receptors with D-APV
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| N |
• despite coordiation defects, mice are not impaired in wide variety of other tests of motor/sensorimotor function
|
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• in conditioning chamber tests with tone/shock (T/S) pairings, mutants show impaired short term context conditioning compared to controls on day 1 of training
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• when placed in chamber 24 hours after T/S training, mice show virtually no freezing indicating impaired contextual fear conditioning compared to controls
• control mice show habituation, displaying decreased freezing time, whereas mutants show potentiation of freezing
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• 24 hours after contextual fear testing, mutants show less freezing behavior in response to auditory tone compared to controls
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• mutants at P32 show impaired spatial learning in Morris water maze tests
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• mice exhibit significantly increased times to climb down pole in pole test
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• reduced swimming speed in Morris water maze trials
|
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• hippocampal slices exposed to aCSF containing 6.5 mM potassium exhibited spontaneous interictal epileptiform bursting at a higher frequency than control slices
(J:116872)
• occasional seizures at 4 weeks of age
(J:167241)
|
|
• at 1 and 3 months, higher numbers of apoptotic cells are detected in neocortex, CA1 and CA3 pyramidal cell layers and dentate gyrus (granular and subgranular layers) compared to control brains
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| tuberous sclerosis | DOID:13515 |
OMIM:PS191100 |
J:167241 , J:134889 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• median survival of 35 days, with no survivors beyond 65 days
(J:121858)
• mice treated with rapamycin or RAD001 (mTOR inhibitor) show 90-100% survival to 80 days of age compared to median survival of 33 days for untreated mutants
(J:136366)
• discontinuation of drug treatment at P30 results in clinical symptom improvement for 1-2 weeks followed by clinical deterioration and death at 79 days for rapamycin-treated and 77 days for RAD001-treated mutants
(J:136366)
|
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• after P5 until death, mutants fail to gain weight at same rate as controls; average maximum weight is 10 grams
|
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• mice develop clinical seizures, spontaneous and some provoked in most part by physical simulation; both types of seizures are mild or severe
• severe seizures are characterized by brief behavioral arrest, followed by several seconds of clonic activity, followed by tonic extensor posturing of trunk and limbs for 15-45 seconds
• after P21, suspension by the tail results in gentle spinning leading severe seizure activity, followed by bradycardia and death
|
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• only mild seizures occur spontaneously, characterized by brief myoclonic jerking of head and torso
|
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• enlarged cells are seen outside cerebral cortex, in other parts of brain including thalamus, hypothalamus and brainstem
• no increased cell loss or degeneration is observed in regions containing anomalous enlarged cells
|
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• brain weight to body weight ratio is significantly greater (2.4-fold) in mutants compared to wild-type; with rapamycin/RAD001 treatment, difference from control is significantly reduced but still observed
|
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• enlarged cells are observed in hilus
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• enlarged cells are seen throughout pyramidal cell layer, particularly in CA3 region
|
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• enlarged ectopic cells are seen outside the CA1-CA3 fields in stratum oriens and stratum radiatum
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• laminar organization is less distinct than in the 6 cortical layers of controls
(J:121858)
• unusually large cells are observed in all six layers in mutants, particularly in layer V; layer of enlarged cells is seen at gray-white matter border throughout cerebral cortex at P21
(J:121858)
• mutants display subset of enlarged pS6-positive cells at base of cortex and in cortical layer V; drug treatment results in marked reduction in size of enlarged cells
(J:136366)
• mild cortical disorganization is observed in mutants with or without rapamycin treatment
(J:136366)
|
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• contains some enlarged cells
|
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• Nissl bodies and filamentous aggregates are often detected in enlarged neurons, prominently in brainstem but rarely in enlarged cortical cells
(J:121858)
• some neurons are aberrantly localized outside primary pyramidal cell layers; ectopic neurons are isolated, not organized into clusters or columns
(J:121858)
• some neurons in somatosensory cortex show 60% increase in soma size relative to controls
(J:121858)
• many pyramidal neurons demonstrate dysplastic features including increased size and thicker dendritic arbors compared to control neurons
(J:121858)
• population of neurons in lateral somatosensory cortex are considerably enlarged compared with those in controls; size is significantly reduced after drug treatment (from 1.8-fold to 1.2-fold), but effect reverses when treatment is stopped
(J:136366)
• in somatosensory cortex, layer V neurons often have major dendrites extending tangentially and diagonally to the pia, in contrast to control neurons which mainly have long apical dendrite oriented directly toward pial surface; rapamycin treatment initiated at P7 does not significantly decrease abnormally oriented dendrite percentage
(J:136366)
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• in mutant brains, neurons appear to be still actively growing after P14-21, whereas wild-type neurons have stopped growing
• this may result in the hypomyelination, due to secondary myelination failure
|
|
• in hippocampal neuron cultures, neuronal dendritic spine density is reduced >20% compared to controls
• with rapamycin treatment, spine density is marginally increased; spine length however is increased 9% compared to treated and untreated controls or untreated mutants
|
|
• hypomyelination is observed in brains of mutants
(J:121858)
• oligodendrocyte number and distribution appears similar to wild-type
(J:121858)
• myelination particularly in cortex is impaired due to decreased myelin production by oligodendrocytes; rapamycin treatment works to restore myelination throughout brain with greatest improvement in cortex and hippocampus
(J:136366)
|
|
• mice aged P21-48 display 3 types of electrographic abnormalities: short spike bursts observed in all mice examined, occasionally spontaneous period of desynchronization with electrodecrement and at low incidence, frequent high-amplitude sharp waves
• interictal (seizure) 1-2 second bursts of high-amplitude 7-8 hertz spikes are observed with high frequency compared with controls; these are without obvious clinical correlate
|
|
• clasping behavior and tremor are significantly ameliorated by rapamycin/RAD001 treatment relative to untreated animals at 30, 60, and 100 days postnatal
|
|
• apparent by P10
|
|
• display posterior limb-clasping behavior when lifted by tail
|
|
• at death, usually in third to fifth postnatal week, mice are found with extensor posture of fore- and hindlimbs
|
|
• develops by by third or fourth postnatal week
|
|
• tail dorsiflexion is exhibited
|
|
• mice show progressive decline in activity with limited mobility by third or fourth postnatal week
|
|
• apparent by P10
|
|
• mice develop clinical seizures, spontaneous and some provoked in most part by physical simulation; both types of seizures are mild or severe
• severe seizures are characterized by brief behavioral arrest, followed by several seconds of clonic activity, followed by tonic extensor posturing of trunk and limbs for 15-45 seconds
• after P21, suspension by the tail results in gentle spinning leading severe seizure activity, followed by bradycardia and death
|
|
• only mild seizures occur spontaneously, characterized by brief myoclonic jerking of head and torso
|
|
• kyphosis is significantly improved in rapamycin/RAD001-treated mice compared with untreated mutants
|
|
• in mutant brains, neurons appear to be still actively growing after P14-21, whereas wild-type neurons have stopped growing
• this may result in the hypomyelination, due to secondary myelination failure
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| tuberous sclerosis | DOID:13515 |
OMIM:PS191100 |
J:136366 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• Background Sensitivity: anterior segment phenotype is severe and fully penetrant compared to a variable phenotype on a mixed background containing NMRI
|
|
• the ciliary body is hypotrophic with a lack of ciliary processes at P18
• ciliary body structure lacks well-defined ciliary processes with the pigmented ciliary epithelium (PCE) and non-pigmented ciliary epithelia (NCE) appearing to coalesce
• Background Sensitivity: the ciliary body phenotype is fully penetrant on this background compared to a variable phenotype on a mixed background containing NMRI
|
|
• the iris exhibits a thickened club-like appearance with atrophic sphincter pupillae instead of an elongated oval structure
• the iris is hypotrophic with a lack of iris extension at P18
• Background Sensitivity: the iris phenotype is fully penetrant on this background compared to a variable phenotype on a mixed background containing NMRI
|
|
• seen in P15 mice
|
|
• shorter cornea and reduced curvature of the cornea
|
|
• anterior eye chamber is reduced in volume
|
|
• the ciliary body and iris fail to undergo morphogenesis as indicated by the absence of ciliary processes and lack of iris extension
|
|
• ciliary margin length is shorter at E18.5 and exhibits a reduced rate of progenitor cell proliferation at E18.5
|
|
• posterior eye segment is larger
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| anterior segment dysgenesis | DOID:0060648 |
OMIM:PS107250 |
J:239666 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• the iris pigment epithelium appears irregular and disorganized
|
|
• Background Sensitivity: severity of anterior segment phenotype is variable, albeit with full penetrance, on a mixed background containing NMRI compared to severe phentoype on a mixed background without NMRI
|
|
• ciliary body is hypotrophic, with ciliary processes in some eyes being underdeveloped, whereas other eyes have barely detectable ciliary processes
|
|
• mice exhibit a disorganized Pax6+ ciliary epithelia that results in indistinct ciliary processes
|
|
• iris exhibits an atrophic sphincter pupillae and size and position of the sphincter pupillae is variable
• the iris appears as a shortened structure completely lacking a dilator pupillae in some animals while normal iris extension is seen in other animals although with dilator pupillae atrophy
|
|
• the iris pigment epithelium appears irregular and disorganized
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• gene expression analysis indicates that fat utilization and glucose production are promoted in mutants
|
|
• plasma triglyceride levels are lower than in wild-type mice, however adiponectin and leptin levels are no different
• mutants do not show an increase in plasma triglyceride levels in response to the high-fat diet as is seen in wild-type mice
|
|
• mutants exhibit mild but significant glucose intolerance
|
|
• mutants exhibit a slight reduction in systemic insulin sensitivity
• insulin levels at 30 minutes following glucose administration are higher in mutants than controls, indicating insulin resistance
• however, fasting plasma glucose and insulin levels are normal
|
| N |
• mutants normally do not exhibit hepatic steatosis, however when fed a high-fat diet and treated with rapamycin, they develop steatosis and show increased levels of hepatic triglycerides
|
|
• mutants develop hepatomegaly
|
|
• increase in hepatocyte cell size
|
|
• hepatocytes are resistant to steatosis induced by a high-fat diet
|
|
• mutants develop hepatomegaly
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• mutants exhibit premature activation of the entire primordial follicle pool with an enhanced rate of oocyte growth and follicular development greater than in either single mutant
|
|
|
• mutants exhibit premature activation of the entire primordial follicle pool with an enhanced rate of oocyte growth and follicular development greater than in either single mutant
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• mutants exhibit premature activation of the entire primordial follicle pool by P23, leading to follicle depletion and premature ovarian failure in early adulthood (2-3 months of age)
• injection with rapamycin reverses the overactivation of primordial follicles, indicative that mTORC1 activity is responsible for increased activation of follicles
|
|
|
• premature ovarian failure in early adulthood (2-3 months of age)
|
|
|
• premature ovarian failure in early adulthood (2-3 months of age)
|
|
• higher levels at 3-4 months of age
|
|
• higher levels at 3-4 months of age
|
|
|
• mutants exhibit premature activation of the entire primordial follicle pool by P23, leading to follicle depletion and premature ovarian failure in early adulthood (2-3 months of age)
• injection with rapamycin reverses the overactivation of primordial follicles, indicative that mTORC1 activity is responsible for increased activation of follicles
|
|
|
• premature ovarian failure in early adulthood (2-3 months of age)
|
|
|
• from 6-27 weeks of age, females produce at most 2 litters of normal size and then become infertile after around 12-13 weeks
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• although some primordial follicles are activated by P23, not all of them are activated as seen in single conditional homozygous Tsc1 mutants, indicating partial reversal of the overactivation of primordial follicles
|
|
|
• although some primordial follicles are activated by P23, not all of them are activated as seen in single conditional homozygous Tsc1 mutants, indicating partial reversal of the overactivation of primordial follicles
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• at P21 and P60
|
|
• flat chest
|
|
• at P21 and P60
|
|
• enlarged
|
|
• immature bony structure is seen at P60
|
|
• classic structure is absent at 4 and 8 weeks of age
• at 1 week of age the primary ossification center is abnormal
|
|
• absent at 4 and 8 weeks of age
|
|
• chrondrogenesis is elevated in the growth plate but hypertrophic chondrocytes are rare
|
|
• at 4 and 8 weeks of age
|
|
• disk height is reduced at 4 and 8 weeks of age
|
|
• smaller and shorter
|
|
• loss of intervertebral space and congenital spinal canal stenosis
• treatment with rapamycin by daily gavage for 4 weeks rescues the spinal deformity
|
|
• micro-CT analysis suggests enhanced thickness
|
|
• micro-CT analysis suggest enhanced density of the trabecular bone
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| spinal disease | DOID:0060564 | J:273713 | ||
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• most mice die before 3 months of age
|
Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB)), Gene Ontology (GO) |
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last database update 04/16/2024 MGI 6.23 |
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