All Phenotypes Kptn<tm1a(EUCOMM)Wtsi> MGI Mouse

behavior/neurological phenotype ( J:343200 )

N	• mice show normal performance in a hippocampus-independent pair-wise discrimination task (Bussey-Saksida chamber) • despite dysregulation of numerous known epilepsy-associated genes in brain tissue, mice show absence of detectable spontaneous seizures

abnormal long-term spatial reference memory ( J:343200 )

• in a Barnes maze assay, mice show a deficit in long-term memory during the second probe test and are on average 12.8% further from the goal box location and spend 17.9% less time in the target zone than wild-type controls

increased anxiety-related response ( J:343200 )

• in a light/dark box test, mice show a 59.6% increase in the time spent in the dark zone and a 45.6% decrease in the frequency of visits to the light zone, indicating a strong anxiety-like phenotype

abnormal response to social novelty ( J:343200 )

• in a social recognition assay, mice show a significantly lower social recognition index on Day 2, when given the choice between investigating a new, unfamiliar mouse and a familiar one (Stimulus A from Day 1) with no preference for the unfamiliar mouse, indicate a memory deficit

increased locomotor activity ( J:343200 )

• in an open-field test, mice show a significantly greater total distance traveled and time spent moving than wild-type controls

abnormal cranium morphology ( J:343200 )

• adult mice exhibit skull shape abnormalities, including overgrowth and deformation

enlarged cranium ( J:343200 )

• adult skulls exhibit an increase in the height, length and width of the brain cavity

• at 16 weeks of age, female and male mice show a 7.7% and 9.2% increase, respectively, in mean intracranial volume relative to wild-type controls

increased cranium height ( J:343200 )

• skull height at the midline is consistently increased along the rostro-caudal extent of the brain cavity (5.2% at Bregma/L1-L7, 4.7% at Lambda/L2-L5)

• height changes are largely due to an increase in the dorsal curvature of the frontal and parietal bones rather than an increase in the dorsoventral length of the lateral skull wall

increased cranium length ( J:343200 )

increased cranium width ( J:343200 )

• adult mice exhibit a 2.56% increase in the width of the brain cavity

frontal bossing ( J:343200 )

• adult mice exhibit dorsal bulging consistent with the changes seen in frontal bossing in humans

frontal bossing ( J:343200 )

• adult mice exhibit dorsal bulging consistent with the changes seen in frontal bossing in humans

megacephaly ( J:343200 )

• mice exhibit severe and progressive macrocephaly

increased brain size ( J:343200 )

• at 16 weeks of age, female and male mice show a 7.9-14.4% increase in total brain area across the three studied coronal sections (section 1 = Bregma +0.98mm, section 2 = Bregma -1.34mm, and section 3 = Bregma -5.80mm), along with enlarged cortices in all areas measured, and enlarged corpus callosum structures

• brain enlargement is mainly due to hypercellularity rather than a change in cell body size

• megalencephaly is postnatal, progressive and may result from an extended period of brain growth

• no significant increase in total brain area is noted at P0 or at 3 weeks of age

small lateral ventricles ( J:343200 )

• lateral ventricles are the only brain regions exhibiting a decreased size (section 1: -36%, section 2: -54%)

increased corpus callosum size ( J:343200 )

• adult mice exhibit increased corpus callosum thicknesses

increased brain internal capsule size ( J:343200 )

• at P0, the total surface area of the internal capsule is increased by 9%

small hippocampus ( J:343200 )

• at P0, the total surface area of the hippocampus is reduced by 11%

• hippocampus development recovers with increasing age but never reaches statistically significant overgrowth during the life of the mouse

increased cerebral cortex cell number ( J:343200 )

• cortical layers II to V show a significant increase in cell number (layer II/III: +21.7%,; layer IV: +20.1%,; layer V: +16.3%)

• however, cell density is not significantly altered across individual layers of the cortex

increased cerebral cortex total cell area ( J:343200 )

• all six cortical layers display an increase in area, largely due to an equivalent increase in the number of cells, notably in layers II to V

• mean cell size is not significantly altered, apart from layer VI showing an 8.8% increase in cell size

increased primary motor cortex size ( J:343200 )

• motor cortex is significantly increased at 16 weeks but not at P0 or at 3 weeks of age

thickened cerebral cortex ( J:343200 )

abnormal nervous system physiology ( J:343200 )

• both adult whole brain and hippocampus exhibit a significant increase in mTOR pathway activity, as indicated by increased phosphorylation of RPS6; activation of mTOR activity is already present at P21

• treatment with rapamycin (an mTOR pathway inhibitor) reduces the excess p-RPS6 signal to well below wild-type levels

abnormal cranium morphology ( J:343200 )

• adult mice exhibit skull shape abnormalities, including overgrowth and deformation

enlarged cranium ( J:343200 )

• adult skulls exhibit an increase in the height, length and width of the brain cavity

• at 16 weeks of age, female and male mice show a 7.7% and 9.2% increase, respectively, in mean intracranial volume relative to wild-type controls

increased cranium height ( J:343200 )

• skull height at the midline is consistently increased along the rostro-caudal extent of the brain cavity (5.2% at Bregma/L1-L7, 4.7% at Lambda/L2-L5)

• height changes are largely due to an increase in the dorsal curvature of the frontal and parietal bones rather than an increase in the dorsoventral length of the lateral skull wall

increased cranium length ( J:343200 )

increased cranium width ( J:343200 )

• adult mice exhibit a 2.56% increase in the width of the brain cavity

frontal bossing ( J:343200 )

• adult mice exhibit dorsal bulging consistent with the changes seen in frontal bossing in humans

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

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

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
autosomal recessive intellectual developmental disorder 41		DOID:0081206	OMIM:615637	J:343200

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

Contributing Projects: 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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