Phenotypes associated with this allele

• Allele Symbol: Vcp⁺
• Allele Name: wild type
• Allele ID: MGI:2432792
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
ht1	Vcp^tm1Itl/Vcp^+	B6.129S-Vcp^tm1Itl	MGI:4849542
ht2	Vcp^tm1.1Hiok/Vcp^+	B6(Cg)-Vcp^tm1.1Hiok	MGI:7284278
ht3	Vcp^em1Kene/Vcp^+	C57BL/6J-Vcp^em1Kene	MGI:7284337

Genotype
MGI:4849542

ht1

• Allelic Composition: Vcp^tm1Itl/Vcp⁺
• Genetic Background: B6.129S-Vcp^tm1Itl

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

muscle

abnormal skeletal muscle fiber morphology ( J:166230 )

• beginning at 9 months, myofibrils exhibit vacuoles unlike in wild-type mice

• at 15 months, myofibrils contain more vacuoles than wild-type cells

• myofibrils exhibit disorganized sarcomere and swelling of mitochondria unlike in wild-type mice

• myofibrils exhibit Tardbp+ (TDP-43) and ubiquitin+ cytoplasmic inclusion bodies unlike in wild-type mice

increased variability of skeletal muscle fiber size ( J:166230 )

centrally nucleated skeletal muscle fibers ( J:166230 )

• at 9 to 10 months and 15 months

progressive muscle weakness ( J:166230 )

• at 6 months and worsening with age, as determined by performance on a rotarod and grip strength test

myopathy ( J:166230 )

• muscles exhibit increased autophagy and apoptosis compared with wild-type muscles

behavior/neurological

behavior/neurological phenotype ( J:166230 )

N • mice exhibit normal short term memory

impaired coordination ( J:166230 )

• at 3 months and worsening with age on a rotarod

decreased grip strength ( J:166230 )

• at 3 months and worsening with age

seizures ( J:166230 )

• in up to 15% of mice

tonic-clonic seizures ( J:166230 )

skeleton

abnormal osteoclast differentiation ( J:166230 )

• bone marrow derived macrophages form more osteoclasts in culture than wild-type cells

increased osteoclast cell number ( J:166230 )

• mice exhibit increased osteoclasts compared with wild-type mice

• bone marrow derived macrophages form more osteoclasts in culture than wild-type cells

increased compact bone thickness ( J:166230 )

decreased trabecular bone connectivity density ( J:166230 )

• trabecular pattern factor is decreased compared to in wild-type mice

decreased bone mass ( J:166230 )

• mice exhibit radiolucency of distal femurs and proximal tibiae compared with wild-type mice

nervous system

seizures ( J:166230 )

• in up to 15% of mice

tonic-clonic seizures ( J:166230 )

abnormal neuron morphology ( J:166230 )

• at 15 month, neurons in the frontal cortex exhibit a Tardbp+ (TDP-43) and ubiquitin+ inclusions unlike in wild-type mice

immune system

abnormal osteoclast differentiation ( J:166230 )

• bone marrow derived macrophages form more osteoclasts in culture than wild-type cells

increased osteoclast cell number ( J:166230 )

• mice exhibit increased osteoclasts compared with wild-type mice

• bone marrow derived macrophages form more osteoclasts in culture than wild-type cells

cellular

abnormal autophagy ( J:166230 )

• muscle tissue exhibits autophagy unlike in wild-type tissue

abnormal osteoclast differentiation ( J:166230 )

• bone marrow derived macrophages form more osteoclasts in culture than wild-type cells

hematopoietic system

abnormal osteoclast differentiation ( J:166230 )

• bone marrow derived macrophages form more osteoclasts in culture than wild-type cells

increased osteoclast cell number ( J:166230 )

• mice exhibit increased osteoclasts compared with wild-type mice

• bone marrow derived macrophages form more osteoclasts in culture than wild-type cells

homeostasis/metabolism

abnormal autophagy ( J:166230 )

• muscle tissue exhibits autophagy unlike in wild-type tissue

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
inclusion body myopathy with Paget disease of bone and frontotemporal dementia		DOID:0050881	OMIM:PS167320	J:166320

Genotype
MGI:7284278

ht2

• Allelic Composition: Vcp^tm1.1Hiok/Vcp⁺
• Genetic Background: B6(Cg)-Vcp^tm1.1Hiok

nervous system

decreased brain weight ( J:308471 )

• in E18 embryos and at age 1 and 3 months

• normal from age 6 months

abnormal cerebral cortex morphology ( J:308471 )

• cytoplasmic ubiquitinated TARDBP aggregates in frontal association cortex and other cortex region neurons at age 6 months

• increased glia cell density in external pyramidal layer of frontal cortex at age 6 months

• increased number of dendrites in external pyramidal layer of frontal cortex at age 6 months

• larger neurons in frontal cortex at age 6 months

• normal in E13 and E15 embryos

abnormal cerebral cortex pyramidal cell morphology ( J:308471 )

• increased number of dendrites in external pyramidal layer of frontal cortex at age 6 months

abnormal stratification in cerebral cortex ( J:308471 )

• thinner layers II-III (CUX1+) and III-V (FOXP1+) at age 6 months

• thicker layer VI (TBR1+) at age 6 months

thin cerebral cortex ( J:308471 )

• in E18 embryos

abnormal frontal lobe morphology ( J:308471 )

• cytoplasmic ubiquitinated TARDBP aggregates in frontal association cortex from age 6 months

• normal in E13 and E15 embryos

abnormal primary motor cortex morphology ( J:308471 )

• cytoplasmic ubiquitinated TARDBP aggregates in M2 motor cortex from age 3 months

decreased dendritic spine number ( J:308471 )

• in layer 1 of dysgranular retrosplenial cortex (RSD) at age 3 months

• increased rate of elimination in layer 1 of dysgranular retrosplenial cortex (RSD) at age 3 months

decreased neuronal stem cell self-renewal ( J:308471 )

• excessive neurogenesis depleting neural stem cells (NSC) pools in ventricular/subventricular zone (VZ/SVZ) in E10 and E15 embryos

behavior/neurological

impaired spatial learning ( J:308471 )

• increased latency to find platform in Morris water maze test from age 6 months

increased anxiety-related response ( J:308471 )

• increased distance traveled in open field test and less time spent in light in light-dark box test from age 6 months

fast extinction of fear memory ( J:308471 )

• impaired fear memory: reduced freezing time in fear-conditioning test from age 12 months

growth/size/body

increased body weight ( J:308471 )

• heavier by age 18 months

microcephaly ( J:308471 )

• developmental microcephaly owing to excessive neurogenesis depleting neural stem cells (NSC) pools in ventricular/subventricular zone (VZ/SVZ) in E10 and E15 embryos

homeostasis/metabolism

impaired DNA repair ( J:308471 )

• slower DNA damage repair

• accumulation of DNA damage in cerebral cortex at ages 3 and 6 months

• accumulation of DNA damage in differentiated neurons and neural stem cells (NSCs) in cerebral cortex from E13 and E15 embryos

cellular

cellular phenotype ( J:308471 )

N • normal equal and unequal division of cell membranes and mitotic plane angle in apical neural stem/progenitor cells in cerebral cortex of E13 embryos

N • normal apoptosis of differentiating neurons and neural stem cells (NSCs) in forebrains of E15 embryos

abnormal endoplasmic reticulum morphology ( J:308471 )

• ER expansion in cortical neurons

abnormal cell cycle checkpoint function ( J:308471 )

• delayed or arrested G1/S transition in embryonic neural stem cells (NSCs) from cerebral cortex of E15 embryos

• elongated G1 phase and total cell cycle time in neural stem cells (NSCs) from forebrains of E15 embryos

• increase in proportion of proliferating cells exiting cell cycle

• normal M phase time in neural stem cells (NSCs) from forebrains of E15 embryos

• normal M phase transition in ventricular/subventricular zone (VZ/SVZ) of E13 and E15 embryos

cellular necrosis ( J:308471 )

• early-stage transcriptional repression-induced atypical cell death (TRIAD) necrosis of neurons in cerebral cortex from ages 1 to 12 months, peaking at 3 months

impaired DNA repair ( J:308471 )

• slower DNA damage repair

• accumulation of DNA damage in cerebral cortex at ages 3 and 6 months

• accumulation of DNA damage in differentiated neurons and neural stem cells (NSCs) in cerebral cortex from E13 and E15 embryos

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
frontotemporal dementia		DOID:9255		J:308471

Genotype
MGI:7284337

ht3

• Allelic Composition: Vcp^em1Kene/Vcp⁺
• Genetic Background: C57BL/6J-Vcp^em1Kene

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:325062 )

N • normal plasma glucose and insulin levels when fed high fat diet (HFD)

N • normal intraperitoneal glucose tolerance test (IPGTT) when fed high fat diet (HFD)

N • normal plasma nonesterified fatty acid (NEFA) and total cholesterol levels when fed high fat diet (HFD)

N • normal liver ATP levels at age 20 weeks when fed high fat diet (HFD)

decreased susceptibility to diet-induced obesity ( J:325062 )

• reduced liver enlargement, weight increase and triglyceride levels when fed high fat diet (HFD)

• reduced size and number of lipid droplets in liver when fed high fat diet (HFD)

increased susceptibility to diet-induced obesity ( J:325062 )

• greater increase in epididymal white adipose tissue (eWAT) mass when fed high fat diet (HFD)

• larger adipocytes in epididymal white adipose tissue (eWAT) when fed high fat diet (HFD)

increased circulating triglyceride level ( J:325062 )

• when fed high fat diet (HFD)

increased insulin sensitivity ( J:325062 )

• as measured by intraperitoneal insulin tolerance test (IPITT) when fed high fat diet (HFD)

growth/size/body

growth/size/body region phenotype ( J:325062 )

N • normal liver and epididymal white adipose tissue (eWAT) weights, liver histology and liver TG content when fed standard diet

decreased body weight ( J:325062 )

• from birth when fed standard diet

• normal when fed high fat diet (HFD) from age 8 weeks

decreased susceptibility to diet-induced obesity ( J:325062 )

• reduced liver enlargement, weight increase and triglyceride levels when fed high fat diet (HFD)

• reduced size and number of lipid droplets in liver when fed high fat diet (HFD)

increased susceptibility to diet-induced obesity ( J:325062 )

• greater increase in epididymal white adipose tissue (eWAT) mass when fed high fat diet (HFD)

• larger adipocytes in epididymal white adipose tissue (eWAT) when fed high fat diet (HFD)

cellular

cellular phenotype ( J:325062 )

N • no signs of ER stress in liver at age 20 weeks when fed high fat diet (HFD)