Phenotypes Associated with This Genotype

Genotype
MGI:6275631

• Allelic Composition: Mdga2^{Tg(Prnp-PFN1*G118V)838Kiaei}/Mdga2⁺
• Genetic Background: involves: C57BL/6N

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

mortality/aging

premature death ( J:241428 )

• average age of death is 202 +/- 30 days, with females reaching end stage of disease sooner than males

behavior/neurological

abnormal motor capabilities/coordination/movement ( J:241428 )

• mice exhibit progressive deterioration of motor function with the onset of symptoms at P120-130 and rapid progression to end-stage disease by P165-210

limb grasping ( J:241428 )

• mice develop gradual hind limb clasping

tremors ( J:241428 )

• symptoms begin as a fine tremor and mice show further tremor development with age

impaired coordination ( J:241428 )

• ability to stay on a rotating rod is impaired, with mice showing shorter latency on the rotarod beginning at P140 and gradually deteriorates such as that mice eventually lead to zero latency

abnormal gait ( J:241428 )

• mice develop gait abnormalities and duck-like walking pattern, spasticity, and an inability to elevate the tail

short stride length ( J:241428 )

• average stride length is reduced at P160 and mice become nonambulatory in final stage of disease

decreased locomotor activity ( J:241428 )

• mice show a gradual decline in locomotion

hindlimb paralysis ( J:241428 )

• mice drag their hind legs at the end stage of disease

spasticity ( J:241428 )

growth/size/body

weight loss ( J:241428 )

• weight loss starts at around P150

nervous system

microgliosis ( J:241428 )

• mice show increased activation of glial cells in lumbar spinal cord regions

abnormal Wallerian degeneration ( J:241428 )

• irregularly shaped, non-circular, shrunken, and collapsed axons are abundant in lumbar ventral roots, and separation and vacuolization of the myelin sheath and shrinkage of axoplasm are seen resembling Wallerian-like degeneration

astrocytosis ( J:241428 )

• mice show increased activation of astrocytes in lumbar spinal cord regions

abnormal motor neuron dendrite morphology ( J:241428 )

• corticospinal motor neurons exhibit multiple apical dendrite abnormalities, such as a vacuole filled dendrites, and varied size and number of dendrites

abnormal neuromuscular synapse morphology ( J:241428 )

• mice show degeneration of neuromuscular junctions, with reduced neuromuscular junction number in tibialis and gastrocnemius muscle and a higher percentage of denervated and reduced innervated muscles

abnormal sciatic nerve morphology ( J:241428 )

• degenerating myelinated axons and glia containing phagocytized myelin in the sciatic nerves of end-stage mice

abnormal ventral spinal root morphology ( J:241428 )

• ventral roots from L1 and L5 spinal vertebrae show degenerative axons and aberrant mitochondria with fragmented outer membranes and irregular cristae

abnormal spinal cord morphology ( J:241428 )

• spinal cord shows mutant profilin 1 aggregation and accumulation of ubiquitinated proteins

• the F/G-actin ratio is reduced in spinal cord lumbar sections, indicating impaired actin polymerization

motor neuron degeneration ( J:241428 )

• loss of lower (ventral horn) and upper (corticospinal motor neurons in layer V) motor neurons

abnormal spinal cord ventral horn morphology ( J:241428 )

• mice show progressive loss of ventral horn spinal neurons

• dysmorphic looking neurons in the ventral horn

• choline acetyltransferase expression is reduced in spinal cord ventral horn neurons

• TDP-43 is more prominent and dense in the neuronal nucleus in the spinal cord ventral horn and higher levels of phosphorylated TDP-43 in the nucleus of spinal cord neurons

axon degeneration ( J:241428 )

• ventral roots from L1 and L5 spinal vertebrae show degenerative axons

• sciatic nerves exhibit degenerating myelinated axons of end-stage mice

abnormal action potential ( J:241428 )

• mice exhibit reduced hind limb compound muscle action potential amplitude and prolonged compound muscle action potential duration in tibialis anterior muscle

hematopoietic system

microgliosis ( J:241428 )

• mice show increased activation of glial cells in lumbar spinal cord regions

homeostasis/metabolism

abnormal Wallerian degeneration ( J:241428 )

• irregularly shaped, non-circular, shrunken, and collapsed axons are abundant in lumbar ventral roots, and separation and vacuolization of the myelin sheath and shrinkage of axoplasm are seen resembling Wallerian-like degeneration

immune system

microgliosis ( J:241428 )

• mice show increased activation of glial cells in lumbar spinal cord regions

limbs/digits/tail

abnormal ankle joint morphology ( J:241428 )

• initial symptoms include the appearance of an angle in the hind limb at the ankle joint where gastrocnemius and tibialis muscle tendons are attached

muscle

skeletal muscle atrophy ( J:241428 )

• in the hind limbs

progressive muscle weakness ( J:241428 )

• mice show progressive hind limb skeletal muscle weakness

skeleton

abnormal ankle joint morphology ( J:241428 )

• initial symptoms include the appearance of an angle in the hind limb at the ankle joint where gastrocnemius and tibialis muscle tendons are attached

kyphosis ( J:241428 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
amyotrophic lateral sclerosis type 18		DOID:0060209	OMIM:614808	J:241428