Phenotypes associated with this allele

• Allele Symbol: Afg3l2^Emv66
• Allele Name: endogenous ecotropic MuLV 66
• Allele ID: MGI:3775617
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Afg3l2^Emv66/Afg3l2^Emv66	FVB.MEV2-Afg3l2^Emv66/TyJ	MGI:3775761
hm2	Afg3l2^Emv66/Afg3l2^Emv66	involves: C57BL/6 * FVB/N * MEV/2Ty	MGI:5476803
ht3	Afg3l2^Emv66/Afg3l2^+	involves: MEV/2Ty	MGI:5696777

Genotype
MGI:3775761

hm1

• Allelic Composition: Afg3l2^Emv66/Afg3l2^Emv66
• Genetic Background: FVB.MEV2-Afg3l2^Emv66/TyJ

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

mortality/aging

postnatal lethality, complete penetrance ( J:132285 )

• mice rarely survive longer than 16 days of age

growth/size/body

decreased body size ( J:132285 )

• mutant mice are significantly smaller than controls at 1 week of age

behavior/neurological

impaired righting response ( J:132285 )

• mice exhibit an inability to turn over when placed on the back

impaired coordination ( J:132285 )

• mice exhibit uncoordinated movements

paralysis ( J:132285 )

• animals are usually totally paralysed at postnatal day 16

nervous system

abnormal neuron morphology ( J:132285 )

• multiple large vacuoles with clear content are present in neuronal cell bodies at P14; mitochondrial defects are seen including displacement of the inner membrane, cristae disruption and increased volume of the intermembrane space

• no evidence of neuronal loss of spinal cord anterior horn motor neurons, sensory dorsal root ganglion neurons, and Purkinje cells is seen

• vacuoles are already present in 76% of the dorsal root ganglion neurons by P1

abnormal axon morphology ( J:132285 )

• large caliber axons are absent from the spinal cord and sciatic nerve

• no evidence for axonal degeneration is seen; total number of axons is similar to controls

• some axonal damage is seen in sciatic nerve including Schwann cell infoldings into the axoplasm and disintegration of adaxonal myein lamellae

• sciatic nerve also contain damaged mitochondria with swollen cristae

abnormal spinal cord white matter morphology ( J:132285 )

• mutant spinal cord shows a reduction in myelinated fiber density with the remaining fibers exhibiting small diameters; no large caliber axons are seen

decreased spinal cord size ( J:132285 )

• mutant spinal cords exhibit a reduced diameter compared to controls

abnormal myelination ( J:132285 )

• at P1, the number of myelinated axons in the corticospinal tract is similar to controls

• by P7, only a few myelinated axons are present in the corticospinal tract of mutant mice

• at P14, most axons in the corticospinal tract are myelinated in control mice whereas in the mutant mice, only 60% of the axons are myelinated and many small unmyelinated axons are present

• at P5, myelination is also delayed in the sciatic nerve, which shows a reduced number of myelinated axons compared to controls

• myelination of the dorsal roots is delayed by P5 and in the ventral roots by P1

• neurofilament content of mutant axons shows a reduced density in mutant mice; it appears in dense clusters with uneven distribution compared to controls

muscle

abnormal skeletal muscle fiber morphology ( J:132285 )

• no signs of inflammation, degeneration or necrosis

• rarely, some muscle fibers show mitochondrial defects

decreased skeletal muscle fiber size ( J:132285 )

• mutant skeletal muscle fibers appear smaller

centrally nucleated skeletal muscle fibers ( J:132285 )

• rarely, some muscle fibers show centrally positioned nuclei

progressive muscle weakness ( J:132285 )

• mice exhibit a rapid loss of motor function in all limbs by P12-14

• mice lose the ability to support their own weight

cellular

cellular phenotype ( J:132285 )

N • no impairment in mitochondrial protein synthesis in different tissues is seen

abnormal respiratory electron transport chain ( J:132285 )

• a decrease in complex activity I in brain or spinal cord-derived mitochondria from mutant mice is seen compared to controls, attributable to a reduced amount of assembles complex I

• a decrease in the amount of complex III is also seen in brain or spinal cord-derived mitochondria from mutant mice

liver/biliary system

liver/biliary system phenotype ( J:132285 )

N • no evidence of abnormal mitochondria morphology in liver sections

Genotype
MGI:5476803

hm2

• Allelic Composition: Afg3l2^Emv66/Afg3l2^Emv66
• Genetic Background: involves: C57BL/6 * FVB/N * MEV/2Ty

cellular

abnormal mitochondrial morphology ( J:193564 )

• defective assembly of mitoribosome from the brains and livers

Genotype
MGI:5696777

ht3

• Allelic Composition: Afg3l2^Emv66/Afg3l2⁺
• Genetic Background: involves: MEV/2Ty

behavior/neurological

limb grasping ( J:151797 )

• mice show limb clasping on tail suspension beginning at 8-10 months of age, with 84.7% of mice showing clasping by 12 months

impaired balance ( J:151797 )

• 4 month old mutants can hardly walk along a beam and make more foot slips compared to wild-type mice

impaired coordination ( J:151797 )

• mice fail to maintain balance on the rotarod at 4 months; performance worsens with age

• when traversing a beam, mutants flatten their abdomen and thorax against the upper surface of the beam instead of adapting a stable upright posture as in wild-type mice

• mutants show increased latency to cross a beam

abnormal locomotor activation ( J:151797 )

• negative-geotaxis reflex is seen at 4 months of age and worsens with age

abnormal gait ( J:151797 )

• altered gait is seen at 4 months of age and worsens with age, such that 12 month old mutants show uncoordinated hindlimb movement

• pelvic elevation is seen at 12 months of age and worsens with age

nervous system

abnormal neuron mitochondrial morphology ( J:151797 )

Purkinje cell degeneration ( J:151797 )

• progressive degeneration and loss of Purkinje cell in the cerebella, beginning at 4 months of age

• Purkinje cells undergo dark cell degeneration, characteristic of excitotoxic injury

• however, motoneuron degeneration in the spinal cord is not seen

abnormal Purkinje cell dendrite morphology ( J:151797 )

• dendritic stalks are abbreviated and hypertrophic with poorly arborized dendritic branches

• enlarged, vacuolated mitochondria in Purkinje cell dendrites

abnormal cerebellar granule layer morphology ( J:151797 )

• at 12 months, mitochondria with destroyed cristae, and organelles with unusual shapes and spatial organization are seen in the granule cell layer

abnormal cerebellar granule cell morphology ( J:151797 )

• aberrant mitochondria are seen in the granule cell layer at 4 months age, the number of which increases over time

• granule cells progressively deteriorate such that at 6 months, many cells show empty cytoplasm and nucleus with condensed chromatin, features of late-stage apoptosis

thin cerebellar granule layer ( J:151797 )

• at 6 and 12 months of age

thin cerebellar molecular layer ( J:151797 )

• reduction in molecular layer thickness at 6 months of age, consisting mostly of Purkinje cell dendrites

gliosis ( J:151797 )

• extensive reactive gliosis in the granule cell layer at 12 months of age

astrocytosis ( J:151797 )

• cerebella exhibits activated astrocytes

cellular

abnormal mitochondrial morphology ( J:151797 )

• Purkinje cells and granule cells show defects in mitochondrial morphology, distribution, and cristae organization by 4 months of age

abnormal mitochondrial crista morphology ( J:151797 )

• cristae structure is abnormal in Purkinje cells and granule cells

abnormal neuron mitochondrial morphology ( J:151797 )

increased mitochondrial size ( J:151797 )

• mitochondria in Purkinje cells and granule cells are larger

abnormal respiratory electron transport chain ( J:151797 )

• Purkinje cells show impaired mitochondrial bioenergetics, with a deficiency in respiratory chain complexes I and III, leading to increased levels of protein carbonylation and mitochondrial reactive oxygen species production

abnormal mitochondrial ATP synthesis coupled electron transport ( J:151797 )

• mice show reduced ATP synthesis in mitochondria from cerebellum, but not from entire brain or spinal cord, at 6 months with pyruvate, glutamate, and succinate/rotenone, which becomes more severe at 12 months of age

oxidative stress ( J:151797 )

• Purkinje cells show increased reactive oxygen species production

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
spinocerebellar ataxia type 28		DOID:0050977	OMIM:610246	J:151797