Phenotypes associated with this allele

• Allele Symbol: Vps54^wr
• Allele Name: wobbler
• Allele ID: MGI:1857091
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Vps54^wr/Vps54^wr	involves: C57BL/6J * C57BL/Fa	MGI:5490471
hm2	Vps54^wr/Vps54^wr	multiple strains	MGI:3614946
ht3	Vps54^Gt(RRI497)Byg/Vps54^wr	involves: 129P2/OlaHsd * C57BL/6J	MGI:3613575

Genotype
MGI:5490471

hm1

• Allelic Composition: Vps54^wr/Vps54^wr
• Genetic Background: involves: C57BL/6J * C57BL/Fa

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

nervous system

increased microglial cell activation ( J:181019 )

• microglia activation accompanies motor neuron degeneration

gliosis ( J:181019 )

• reactive gliosis accompanies motor neuron degeneration

abnormal GABAergic neuron morphology ( J:181019 )

• decrease in density of parvalbumin-positive neurons in layer 5 of the primary motor cortex

• decrease in density of somatostatin-positive neurons in layer 5 of the primary motor cortex

• decrease in optical density of GABAergic synaptic boutons as assessed by VGAT staining in layer 5 of the primary motor cortex

motor neuron degeneration ( J:181019 )

abnormal synaptic bouton morphology ( J:181019 )

• decrease in optical density of GABAergic synaptic boutons as assessed by VGAT staining in layer 5 of the primary motor cortex

abnormal GABAergic neuron physiology ( J:181019 )

• layer 5 pyramidal neurons exhibit increased excitability as a result of decreased GABAergic inhibition

abnormal GABA-mediated receptor currents ( J:181019 )

• mutant mice exhibit a down regulation in phasic and tonic GABA(a) receptor-mediated currents

• mice exhibit an 87% reduction in average tonic current densities (pA/pF) as compared to controls

• input resistance in layer 5 pyramidal neurons is increased in mutant mice as compared to controls

• current threshold is significantly lower in mutant mice, however polarization voltage is similar between mutant and control

abnormal inhibitory postsynaptic currents ( J:181019 )

• individual spontaneous inhibitory post synaptic currents (sIPSC) display smaller amplitudes, however mean amplitude is not statistically different in whole-cell voltage-clamp recordings from layer 5 pyramidal neurons

• sIPSC frequency is 28% lower than controls

abnormal miniature inhibitory postsynaptic currents ( J:181019 )

• whole cell recordings of miniature IPSC (mIPSC) in layer 5 pyramidal neurons detect an increase in weighted decay time constant, but no differences in amplitude or rise time

decreased miniature inhibitory postsynaptic current frequency ( J:181019 )

• mIPSC frequency is 36% lower than controls

muscle

progressive muscle weakness ( J:181019 )

• mice develop muscle weakness in the forelimbs beginning at 3-4 weeks

immune system

increased microglial cell activation ( J:181019 )

• microglia activation accompanies motor neuron degeneration

hematopoietic system

increased microglial cell activation ( J:181019 )

• microglia activation accompanies motor neuron degeneration

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
amyotrophic lateral sclerosis type 1		DOID:0060193	OMIM:105400	J:181019 , J:196432

Genotype
MGI:3614946

hm2

• Allelic Composition: Vps54^wr/Vps54^wr
• Genetic Background: multiple strains

mortality/aging

premature death ( J:165 )

• very reduced viability

growth/size/body

facial muscle atrophy ( J:5102 )

• atrophy of facial muscle gives a pointed appearance to the snout and results in the ears being laid back

upturned snout ( J:6388 )

• upward pointed snout

decreased body weight ( J:1563 , J:5102 , J:6388 )

• at 30 days of age (J:1563)

• 47% normal (J:1563)

behavior/neurological

limb grasping ( J:5102 , J:6388 )

• unusual clasping of feet when suspended by tail (J:6388)

tremors ( J:165 , J:5102 )

• fine tremors of the head (J:5102)

abnormal grip strength ( J:5102 )

• in forepaws

• muscle weakness by fourth or fifth week

abnormal posture ( J:5102 )

• head and anterior trunk held lower than normal

abnormal gait ( J:1563 , J:5102 , J:6388 )

• by 30 days of age (J:1563)

• high stepping and unsteady (J:5102)

• eventually walk on dorsum of forepaws due to the inability to extend the paws at the wrist (J:5102)

• ultimately they push the body along using their hind legs only (J:5102)

forelimb paralysis ( J:165 , J:1563 )

• paralysis primarily affects forelimbs (J:165)

• clasping of front paws and difficulties using front legs (J:1563)

nervous system

abnormal nervous system morphology ( J:35069 )

• brain stem and spinal cord through the thoracic region weighs 62-68% of controls

• cross section area of spinal cord 75-80% of normal

abnormal astrocyte morphology ( J:18368 )

• small numbers of GFAP positive cells in the anterior horn of the spinal cord at 1 month of age and found throughout the gray matter by 10 months

• astrocyte processes perpendicular to surface of cord rather than parallel as in controls

• GFAP reactive material gradually increases from 2 to 5 months of age

gliosis ( J:1563 )

• hypertrophy

abnormal motor neuron morphology ( J:5102 , J:19087 )

• eccentric nuclei (J:5102)

• enlarged soma (J:19087)

• poorly stained Nissl bodies (J:19087)

• reduced numbers of dendrites (J:19087)

motor neuron degeneration ( J:5102 , J:6238 , J:6388 , J:19087 )

• in brain stem and spinal cord but not basal ganglia or cerebral cortex (J:5102)

• progressive denervation of skeletal muscle (J:5102)

• sprouting from myelinated part of preterminal axons and nerve fibers innervate several muscle fibers (J:5102)

• reduced numbers of motor nerves in affected muscle (J:5102)

• vacuolated neurons develop in the cervical spinal cord with much larger surface areas in x-section and smaller nuclear areas (J:6238)

• normal neurons are smaller in x-section but with normal nuclear areas (J:6238)

• protein synthesis reduced in both types of neurons (J:6238)

• vacuolar degeneration of motoneurons also in the lower brain stem (cerebellar, reticular, vestibular, cortical, and olfactory involvement variable) (J:6388)

• number of degenerating neurons increases with development of disease, none before onset of symptoms (J:19087)

abnormal spinal nerve morphology ( J:5331 )

• loss of large diameter nerve fibers in the median nerve

abnormal sciatic nerve morphology ( J:5331 )

• loss of large diameter nerve fibers

abnormal nervous system physiology ( J:5525 )

abnormal myelination ( J:5331 )

• numbers of myelinated nerve fibers in the nerves to the arm and in the nerve to the tibialis anterior muscle were reduce 67-82%

demyelination ( J:5525 )

• in conjunction with dissolution of axoplasm and nerve degeneration

abnormal axonal transport ( J:8186 , J:14361 )

• impaired slow axonal transport affecting neurofilament proteins more than tubulin and actin (J:8186)

• fast axonal transport rate reduced 25% (J:14361)

abnormal CNS synaptic transmission ( J:3719 , J:15226 , J:35070 )

• levels of thyrotropin releasing hormone in the cervical spinal cord increase with progression of disease (J:3719)

• early increases in substance P in the hypothalamus, later increases in spinal cord and midbrain (J:3719)

• variable levels of Met- and Leu-enkephalin over the course of disease progression (J:3719)

• greater numbers of thyrotrophin releasing hormone neuronal processes in the ventrolateral horn of the spinal cord but decreasing with age (J:15226)

• reduced acetylcholinesterase containing cells in the ventral horn of the spinal cord (J:35070)

• substance P elevated in the ventral horn of the spinal cord early but becoming less as the disease progresses (J:35070)

muscle

abnormal skeletal muscle fiber morphology ( J:5102 )

• enlargement of sarcolemmal nuclei which migrate to the center of the muscle fiber

• muscle fibers eventually decrease in diameter

• deposition of fat between atrophied muscle fibers

muscular atrophy ( J:5102 , J:6388 )

• lose of ability to extend paws at wrist (J:5102)

• atrophy of facial muscle gives a pointed appearance to the snout and results in the ears being laid back (J:5102)

• muscle atrophy seen by 6-7 weeks of age (J:5102)

• neurogenic atrophy seen in muscles of mastication, neck, shoulder girdle, and intercostals (J:6388)

facial muscle atrophy ( J:5102 )

• atrophy of facial muscle gives a pointed appearance to the snout and results in the ears being laid back

abnormal muscle physiology ( J:5102 )

muscle weakness ( J:5102 )

• by fourth or fifth week

• particularly involves forelimbs

reproductive system

asthenozoospermia ( J:1563 )

♂ • sperm motility reduced to occasional trembling of the tail

decreased testis weight ( J:1563 )

♂ • testis weight 72% of normal

abnormal gametogenesis ( J:1563 )

oligozoospermia ( J:1563 )

♂ • sperm numbers 70-80% of controls

globozoospermia ( J:1563 )

♂ • lack of intact acrosome

♂ • round sperm heads

infertility ( J:165 , J:6388 )

• both sexes sterile (J:165)

homeostasis/metabolism

decreased circulating estrogen level ( J:6029 )

• decreased levels in both sexes

abnormal nucleotide metabolism ( J:6029 )

• cGMP levels decreased 80% in cervical spinal cord, 56% in the cerebellum, and 29% in the cortex

craniofacial

facial muscle atrophy ( J:5102 )

• atrophy of facial muscle gives a pointed appearance to the snout and results in the ears being laid back

upturned snout ( J:6388 )

• upward pointed snout

liver/biliary system

abnormal hepatocyte morphology ( J:6388 )

• vacuolar changes in hepatocytes

cellular

abnormal cell morphology ( J:5525 )

• all in degenerating neurons

• increase in randomly organized neuronal cytoplasmic microtubules, filaments or smooth endoplasmic reticulum

• membrane bound dense bodies and /or lipid droplets

oligozoospermia ( J:1563 )

♂ • sperm numbers 70-80% of controls

globozoospermia ( J:1563 )

♂ • lack of intact acrosome

♂ • round sperm heads

abnormal endoplasmic reticulum morphology ( J:5525 )

• reduction and disorganization of rough endoplasmic reticulum

abnormal lysosome morphology ( J:5525 )

• increased numbers of lysosomes and autophagic vacuoles

asthenozoospermia ( J:1563 )

♂ • sperm motility reduced to occasional trembling of the tail

endocrine/exocrine glands

decreased testis weight ( J:1563 )

♂ • testis weight 72% of normal

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Werdnig-Hoffmann disease		DOID:13137	OMIM:253300	J:6388

Genotype
MGI:3613575

ht3

• Allelic Composition: Vps54^{Gt(RRI497)Byg}/Vps54^wr
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6J

growth/size/body

decreased body weight ( J:104824 )

behavior/neurological

decreased grip strength ( J:104824 )

• reduced