Phenotypes Associated with This Genotype

Genotype
MGI:6188926

• Allelic Composition: Opa1^tm1.1Geno/Opa1⁺
• Genetic Background: involves: 129S2/SvPas

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

vision/eye

abnormal retina ganglion cell morphology ( J:237963 )

• loss of retinal ganglion cell axons at 16 months of age

retina ganglion cell degeneration ( J:237963 )

• the number of retinal ganglion cell somas is decreased, reaching a 40% and 50% reduction at 9 and 16 months of age, respectively

abnormal optic nerve morphology ( J:237963 )

• optic nerves exhibit axonal alterations, which include general autophagy with typical lamellar bodies composed of double membrane structures corresponding to fused lysosomes and phagosomes

abnormal visual evoked potential ( J:237963 )

• visual evoked potential shows a progressive increase in latencies and a non-significant reduction in amplitudes, reaching 12% and 20% increase in the N- and P-wave, respectively, at 13 months, indicating progressive visual failure

• however, electroretinogram profiles are not altered

abnormal vision ( J:237963 )

• mice develop progressive visual failure

hearing/vestibular/ear

increased or absent threshold for auditory brainstem response ( J:237963 )

• mice do not show differences in auditory function at 3 months of age showing an mean auditory brainstem response thresholds of about 27 dB sound pressure level, but by 5 months of age, mice show a significant 30 dB auditory brainstem response threshold elevation at the highest frequency of 32 kHz and by 11 months of age, mice are severely deaf with a mean auditory brain stem response threshold of 59 dB sound pressure level

deafness ( J:237963 )

• mice are severely deaf by 11 months of age

behavior/neurological

ataxia ( J:237963 )

• in the CatWalk test, mice show a decrease in the front and hind paws print area, with hind paws more severely affected showing a 40% reduction for the left paw

• females show a reduced footprint maximum intensity, especially on the left ipsilateral side, while males show an increase in the maximum intensity of the front paws, suggesting that males and females compensate differently in their hind paw locomotion

• male mice show an increase in the duration of the front paws stance phase, spending more time on the front paw, while females show a general decrease of the stance phase affecting more the left hind paw

impaired coordination ( J:237963 )

• mice show normal behavior before 5 months of age, but at 5 and 11 months, mice show increasing difficulties in remaining on the rotating bar and fall down more rapidly than controls

cardiovascular system

abnormal cardiac muscle tissue morphology ( J:237963 )

• 5 month old cardiac muscles show aberrant structural conformation of myofibrils with large punctuated mitochondria

• 23% fewer mitochondria in cardiac muscle at 5 months of age

• 12% larger mitochondria in cardiac muscle at 5 months of age

decreased heart weight ( J:237963 )

• at 5 months of age

cellular

abnormal mitochondrial morphology ( J:237963 )

• glycolytic fibers exhibit mitochondrial degeneration characterized by lysosome-like structures localized inside the vacuolated matrix

• neuronal tissues show a mild increase in mitochondrial DNA content which becomes significant in the optic nerve

decreased muscle fiber mitochondrial DNA content ( J:237963 )

• muscles have a mild decrease in mitochondrial DNA amounts, while heart shows a 54% decrease

• however, no mitochondrial DNA deletions are seen in glycolytic muscle, retina and heart

disorganized mitochondrial cristae ( J:237963 )

• in glycolytic fibers, mitochondria show loss of cristae organization

• in oxidative fibers, subsarcolemmal mitochondrial aggregates are seen with densely packed cristae, combined with some lipid droplets

abnormal mitochondrial shape ( J:237963 )

• in glycolytic fibers, mitochondria have a swollen and vacuolated shape, with loss of cristae organization

decreased mitochondrial number ( J:237963 )

• 23% fewer mitochondria in cardiac muscle at 5 months of age

increased mitochondrial number ( J:237963 )

• glycolytic and oxidative muscle fibers of 5 month old mice show an increase in the number of mitochondria

increased mitochondrial size ( J:237963 )

• glycolytic and oxidative muscle fibers of 5 month old mice show an increase in size of mitochondria

• 12% larger mitochondria in cardiac muscle at 5 months of age

abnormal autophagy ( J:237963 )

• glycolytic and oxidative muscle fibers show increased mitochondria in phagolysosomes undergoing mitophagy and general autophagy

• 6-fold increase in autophagic structures (autophagy, mitophagy, and vacuolated mitochondria) in 5 month old glycolytic fibers which are still present at 16 months, whereas oxidative fibers show only a slight increase of these structures with age

• nerves from central and peripheral systems show autophagic axonal degenerations preceding myelin alterations in young mice

abnormal mitophagy ( J:237963 )

• mice exhibit an increase in mitophagy, with mitochondria seen inside phagolysosomes in both glycolytic and oxidative muscle fibers

abnormal mitochondrial physiology ( J:237963 )

• mitochondrial dysfunction in the retina, optic nerve, and glycolytic muscle

• at 5 months of age, a 46% decrease in complex IV cytochrome oxidase activity is seen in the retina

• at 11 months of age, a 21% and 20% decrease in complex IV cytochrome oxidase activity is seen in the optic nerve and in glycolytic muscle, respectively

• 44% reduction in the cytochrome oxidase maximal respiration rate in glycolytic muscle is seen before the reduced cytochrome oxidase enzymatic activity

• however, mitochondrial enzymatic activity and cytochrome oxidase functionality are not altered in oxidative muscles (soleus, heart) and the brain

homeostasis/metabolism

abnormal autophagy ( J:237963 )

• glycolytic and oxidative muscle fibers show increased mitochondria in phagolysosomes undergoing mitophagy and general autophagy

• 6-fold increase in autophagic structures (autophagy, mitophagy, and vacuolated mitochondria) in 5 month old glycolytic fibers which are still present at 16 months, whereas oxidative fibers show only a slight increase of these structures with age

• nerves from central and peripheral systems show autophagic axonal degenerations preceding myelin alterations in young mice

abnormal mitophagy ( J:237963 )

• mice exhibit an increase in mitophagy, with mitochondria seen inside phagolysosomes in both glycolytic and oxidative muscle fibers

increased creatine level ( J:237963 )

• increase in total creatine levels in the cerebellum

abnormal enzyme/coenzyme activity ( J:237963 )

• at 5 months of age, a 46% decrease in complex IV cytochrome oxidase activity is seen in the retina

• at 11 months of age, a 21% and 20% decrease in complex IV cytochrome oxidase activity is seen in the optic nerve and in glycolytic muscle, respectively

muscle

abnormal cardiac muscle tissue morphology ( J:237963 )

• 5 month old cardiac muscles show aberrant structural conformation of myofibrils with large punctuated mitochondria

• 23% fewer mitochondria in cardiac muscle at 5 months of age

• 12% larger mitochondria in cardiac muscle at 5 months of age

abnormal muscle fiber morphology ( J:237963 )

• 5 month old mice show alterations of the muscle ultrastructure in both glycolytic and oxidative fibers, with an increase in the number and size of mitochondria

decreased muscle fiber mitochondrial DNA content ( J:237963 )

• muscles have a mild decrease in mitochondrial DNA amounts, while heart shows a 54% decrease

• however, no mitochondrial DNA deletions are seen in glycolytic muscle, retina and heart

abnormal sarcomere morphology ( J:237963 )

• loss of myofibrils in cardiac muscle that gives rise to sarcomere disorganization, with large zones of autophagic and mitophagic materials

nervous system

dilated fourth ventricle ( J:237963 )

• 4 of 8 mice at 11 months of age exhibit dilatation of the fourth ventricle, with 2 of 8 mice showing dilatation of both the lateral and fourth ventricles

abnormal lateral ventricle morphology ( J:237963 )

• lateral ventricle area is increased

dilated lateral ventricle ( J:237963 )

• 5 of 8 mice at 11 months of age exhibit lateral ventricle dilatation, with 2 of 8 mice showing dilatation of both the lateral and fourth ventricles

abnormal cerebellum morphology ( J:237963 )

• cerebellum maximal length is decreased

cerebellum atrophy ( J:237963 )

• 7 of 8 mice exhibit cerebral and/or cerebellar atrophies

abnormal retina ganglion cell morphology ( J:237963 )

• loss of retinal ganglion cell axons at 16 months of age

retina ganglion cell degeneration ( J:237963 )

• the number of retinal ganglion cell somas is decreased, reaching a 40% and 50% reduction at 9 and 16 months of age, respectively

abnormal optic nerve morphology ( J:237963 )

• optic nerves exhibit axonal alterations, which include general autophagy with typical lamellar bodies composed of double membrane structures corresponding to fused lysosomes and phagosomes

abnormal sciatic nerve morphology ( J:237963 )

• sciatic nerve degeneration is seen starting at 5 months, characterized by presence of hyper dense autophagic axons and myelin degeneration that increases with age

• at 16 months of age, a 30% loss of axons is seen in sciatic nerves, with remaining exons showing a 10% increase of their G-ratio

axon degeneration ( J:237963 )

• at 5 months of age, optic nerves show a premature increase in axonal degenerations which are highly significant by 16 months of age

• at 16 months of age, a 30% loss of axons is seen in sciatic nerves

demyelination ( J:237963 )

• 16 month old mice exhibit demyelination, with a 6% decrease in myelin thickness

• myelin degeneration leads to myelin sheath vacuolization, followed by complete disintegration of myelin layers and axons

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
optic atrophy		DOID:5723	OMIM:PS165500	J:237963