Phenotypes Associated with This Genotype

Genotype
MGI:3802545

• Allelic Composition: Tsc1^tm1Djk/Tsc1^tm1.1Djk; Tg(Syn1-cre)671Jxm/0
• Genetic Background: involves: 129S4/SvJae * C57BL/6 * CBA

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

mortality/aging

premature death ( J:121858 , J:136366 )

• 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)

growth/size/body

slow postnatal weight gain ( J:121858 )

• after P5 until death, mutants fail to gain weight at same rate as controls; average maximum weight is 10 grams

nervous system

seizures ( J:121858 )

• 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

sporadic seizures ( J:121858 )

• only mild seizures occur spontaneously, characterized by brief myoclonic jerking of head and torso

abnormal brain morphology ( J:121858 )

• 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

increased brain weight ( J:136366 )

• 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

abnormal dentate gyrus morphology ( J:121858 )

• enlarged cells are observed in hilus

abnormal hippocampus pyramidal cell layer ( J:121858 )

• enlarged cells are seen throughout pyramidal cell layer, particularly in CA3 region

abnormal hippocampus region morphology ( J:121858 )

• enlarged ectopic cells are seen outside the CA1-CA3 fields in stratum oriens and stratum radiatum

abnormal cerebral cortex morphology ( J:121858 , J:136366 )

• 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)

abnormal neocortex morphology ( J:121858 )

• contains some enlarged cells

abnormal neuron morphology ( J:121858 , J:136366 )

• 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)

abnormal neuron differentiation ( J:121858 )

• 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

abnormal dendrite morphology ( J:136366 )

• 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

abnormal myelination ( J:121858 , J:136366 )

• 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)

abnormal brain wave pattern ( J:121858 )

• 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

behavior/neurological

abnormal involuntary movement ( J:136366 )

• clasping behavior and tremor are significantly ameliorated by rapamycin/RAD001 treatment relative to untreated animals at 30, 60, and 100 days postnatal

increased startle reflex ( J:121858 )

• apparent by P10

limb grasping ( J:121858 )

• display posterior limb-clasping behavior when lifted by tail

tremors ( J:121858 )

• progressive high-frequency trunk and limb tremor apparent by P10

abnormal limb posture ( J:121858 )

• at death, usually in third to fifth postnatal week, mice are found with extensor posture of fore- and hindlimbs

hunched posture ( J:121858 )

• develops by by third or fourth postnatal week

straub tail ( J:121858 )

• tail dorsiflexion is exhibited

decreased locomotor activity ( J:121858 )

• mice show progressive decline in activity with limited mobility by third or fourth postnatal week

hyperactivity ( J:121858 )

• apparent by P10

seizures ( J:121858 )

• 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

sporadic seizures ( J:121858 )

• only mild seizures occur spontaneously, characterized by brief myoclonic jerking of head and torso

skeleton

abnormal spine curvature ( J:136366 )

• kyphosis is significantly improved in rapamycin/RAD001-treated mice compared with untreated mutants

cellular

abnormal neuron differentiation ( J:121858 )

• 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