Phenotypes associated with this allele

• Allele Symbol: Vcp^tm1Itl
• Allele Name: targeted mutation 1, inGenious Targeting Laboratory
• Allele ID: MGI:4849540
• Summary: 2 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Vcp^tm1Itl/Vcp^tm1Itl	involves: 129S6/SvEvTac	MGI:5500068
ht2	Vcp^tm1Itl/Vcp^+	B6.129S-Vcp^tm1Itl	MGI:4849542

Genotype
MGI:5500068

hm1

• Allelic Composition: Vcp^tm1Itl/Vcp^tm1Itl
• Genetic Background: involves: 129S6/SvEvTac

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

mortality/aging

postnatal lethality, complete penetrance ( J:191963 )

• lethality is seen from birth to 21 days of age

growth/size/body

decreased body size ( J:191963 )

• small at birth and remain small

decreased body weight ( J:191963 )

postnatal growth retardation ( J:191963 )

• severe

behavior/neurological

decreased grip strength ( J:191963 )

• mutants are unable to complete the grip strength test due to severe muscle weakness

muscle

abnormal sarcomere morphology ( J:191963 )

• quadriceps muscles show abnormal sarcomeric architecture

abnormal skeletal muscle morphology ( J:191963 )

• increase in endomysial space

• quadriceps muscles show abnormal mitochondrial proliferation with large megaconia and disrupted cristae

abnormal skeletal muscle fiber morphology ( J:191963 )

• increase in the number of internal nucleation and splitting myofibers

• myofibrils contain ubiquitin aggregates and inclusions and small angular muscle fibers contain TDP-43 positive sarcoplasmic inclusions

• infiltration of triglycerides and lipids in quadriceps muscle fibers

skeletal muscle fiber necrosis ( J:191963 )

increased variability of skeletal muscle fiber size ( J:191963 )

• wide variation in fiber size

centrally nucleated skeletal muscle fibers ( J:191963 )

decreased skeletal muscle mass ( J:191963 )

skeletal muscle endomysial fibrosis ( J:191963 )

muscle weakness ( J:191963 )

• poor mobility due to muscle weakness

myopathy ( J:191963 )

• myopathic changes in the bilateral tibialis anterior, bilateral hamstrings and bilateral medial gastrocnemius, and unilateral thoracic paraspinal muscles

• muscles show abnormal motor units and myotonic discharge and a reduction in recruitment and interference patterns

• muscles show increased autophagy

cardiovascular system

abnormal heart morphology ( J:191963 )

• enlarged vacuoles, dilated vascular channels, and abnormal architecture of the channels in the heart

• however, ventricle wall thickness and mass are normal and function appears normal

cellular

abnormal mitochondrial crista morphology ( J:191963 )

• mitochondrial cristae are disrupted in quadriceps muscles

abnormal autophagy ( J:191963 )

• in muscle tissue

skeletal muscle fiber necrosis ( J:191963 )

increased mitochondrial fission ( J:191963 )

• quadriceps muscles show abnormal mitochondrial proliferation

integument

focal hair loss ( J:191963 )

• hairless patches of skin resembling ichthyosis-like thickening

limbs/digits/tail

abnormal limb bone morphology ( J:191963 )

• non-symmetrical Paget-like bone lesions of the right hind limb bone

nervous system

abnormal brain morphology ( J:191963 )

• brain shows absence of well-defined synaptic complexes, post-synaptic enlargement and vesicular degeneration

• perinuclear and cytosolic accumulation of ubiquitin-positive deposits are seen in the brain

gliosis ( J:191963 )

• increase in GFAP staining suggesting gliosis

motor neuron degeneration ( J:191963 )

• rapid motor neuron degeneration in spinal cords

skeleton

abnormal limb bone morphology ( J:191963 )

• non-symmetrical Paget-like bone lesions of the right hind limb bone

kyphosis ( J:191963 )

homeostasis/metabolism

abnormal autophagy ( J:191963 )

• in muscle 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:191963

Genotype
MGI:4849542

ht2

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

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