Phenotypes associated with this allele

• Allele Symbol: Sod1^tm1Leb
• Allele Name: targeted mutation 1, Russell M Lebovitz
• Allele ID: MGI:1857873
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Sod1^tm1Leb/Sod1^tm1Leb	B6;129S-Sod1^tm1Leb/J	MGI:3580495
hm2	Sod1^tm1Leb/Sod1^tm1Leb	involves: 129S7/SvEvBrd * C57BL/6	MGI:3820405
hm3	Sod1^tm1Leb/Sod1^tm1Leb	involves: 129S7/SvEvBrd-Hprt^b-m2 * C57BL/6	MGI:6382796
ht4	Sod1^tm1Leb/Sod1^+	B6;129S-Sod1^tm1Leb/J	MGI:3580496

Genotype
MGI:3580495

hm1

• Allelic Composition: Sod1^tm1Leb/Sod1^tm1Leb
• Genetic Background: B6;129S-Sod1^tm1Leb/J

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

hearing/vestibular/ear

thin stria vascularis ( J:102419 )

• at 15 months, homozygotes display a significantly thinner stria vascularis in the apical turn relative to heterozygous or wild-type mice

• however, no differences in stria vascularis thickness are noted in the apical turn at 7-9 months

increased or absent threshold for auditory brainstem response ( J:102419 )

• at 12 and 15 months, homozygotes exhibit significantly increased ABR thresholds for clicks and tone pip stimuli at 8, 16 and 32 kHz relative to C57BL/6, wild-type or heterozygous mice; however, no differences are noted at 7-9 months

• at 12 months, homozygotes show an ~20 dB elevation in ABR thresholds at 32 kHz relative to C57BL/6 control mice; the latter have ABR thresholds that are ~10 dB higher than those in wild-type or heterozygous mice

deafness ( J:102419 )

• at 12 and 15 months, homozygotes exhibit an earlier and significantly greater hearing loss than age-matched C57BL/6, wild-type or heterozygous mice

nervous system

decreased retina ganglion cell number ( J:181434 )

• number of cells in the retinal ganglion cell layer is reduced in 24 week old mutants but not at 8 weeks of age, indicating a progressive reduction

• however, photoreceptor cell death is not seen at 24 weeks of age

cochlear ganglion degeneration ( J:102419 )

• starting at 7-9 months, homozygotes display severe progressive degeneration of spiral ganglion cells in all cochlear turns

• in homozygotes, the magnitude of ganglion cell loss is greater than that of C57BL/6 control mice, esp. above the basal turn

vision/eye

abnormal retina ganglion layer morphology ( J:181434 )

• level of reactive oxygen species (ROS) in the retinal ganglion cell layer is higher in 24-week old mutants than in wild-type mice

decreased retina ganglion cell number ( J:181434 )

• number of cells in the retinal ganglion cell layer is reduced in 24 week old mutants but not at 8 weeks of age, indicating a progressive reduction

• however, photoreceptor cell death is not seen at 24 weeks of age

abnormal retina nerve fiber layer morphology ( J:181434 )

• 24 week old mutants exhibit thinning of the nerve fiber layer

abnormal eye electrophysiology ( J:181434 )

• the amplitude of pattern electroretinogram (ERG) is reduced in 24 week old mutants, although dark-adapted and cone ERGs show no impairment, indicating impaired function of retinal ganglion cells

• however, the intraocular pressure is normal

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
low tension glaucoma		DOID:13544		J:181434

Genotype
MGI:3820405

hm2

• Allelic Composition: Sod1^tm1Leb/Sod1^tm1Leb
• Genetic Background: involves: 129S7/SvEvBrd * C57BL/6

reproductive system

abnormal ovary morphology ( J:64299 )

♀ • at 12 weeks of age, increased stromal cell proliferation is noted in the center of the mutant ovary

decreased corpora lutea number ( J:64299 )

♀

decreased mature ovarian follicle number ( J:64299 )

♀ • while normal-appearing primary follicles and some small antral follicles are present, only a few large antral follicles and corpora lutea are observed

impaired ovarian folliculogenesis ( J:64299 )

♀ • at 6-12 weeks of age, female homozygotes show limited follicular development beyond the early antral follicle stage

small ovary ( J:64299 )

♀ • homozygous mutant ovaries are often smaller than wild-type ovaries

female infertility ( J:64299 )

♀ • 5 of 16 female homozygotes failed to become pregnant over a 2-6 month period

reduced female fertility ( J:64299 )

♀ • female homozygotes survive to adulthood and appear to show normal sexual differentiation but are subfertile

♀ • whereas breeding of 5 female heterozygotes with male heterozygotes over a 6 month period produced an average of 1.0 litter/month, only 11 of 16 female homozygotes became pregnant over a 2-6 month period averaging 0.23 litters/month

♀ • however, mutant and control females were shown to produce a similar number of eggs upon pharmacological superovulation

♀ • in contrast to females, male homozygotes are fertile with normal testicular morphology

decreased litter size ( J:64299 )

• over a 2-6 month period, female homozygotes produced a significantly decreased average litter size relative to female heterozygotes (2.7 vs 8.6 offspring/litter, respectively)

endocrine/exocrine glands

abnormal Meibomian gland morphology ( J:219024 )

• increase in periglandular fibrosis from 10 to 50 weeks of age

abnormal Meibomian gland acinus morphology ( J:219024 )

• decrease in meibomian gland glandular acinar density from 10 to 50 weeks of age

• accumulation of large lipid droplets in the acinar units of meibomian glands of 50 weeks of age; lipid droplets become larger in size and increase in number from 10 to 50 weeks of age

abnormal ovary morphology ( J:64299 )

♀ • at 12 weeks of age, increased stromal cell proliferation is noted in the center of the mutant ovary

decreased corpora lutea number ( J:64299 )

♀

decreased mature ovarian follicle number ( J:64299 )

♀ • while normal-appearing primary follicles and some small antral follicles are present, only a few large antral follicles and corpora lutea are observed

impaired ovarian folliculogenesis ( J:64299 )

♀ • at 6-12 weeks of age, female homozygotes show limited follicular development beyond the early antral follicle stage

small ovary ( J:64299 )

♀ • homozygous mutant ovaries are often smaller than wild-type ovaries

abnormal Meibomian gland physiology ( J:219024 )

• increase in apoptosis within the meibomian glands at 50 weeks of age

Meibomian gland inflammation ( J:219024 )

• increase in periglandular inflammatory infiltrates from 10 to 50 weeks of age

homeostasis/metabolism

suppressed circulating follicle stimulating hormone level ( J:64299 )

• adult female homozygotes exhibit suppressed serum FSH levels relative to control females (38.5 +/- 3.1 ng/ml vs 105.0 +/- 17.3 ng/ml, respectively), as shown by RIA analysis

decreased circulating luteinizing hormone level ( J:64299 )

• adult female homozygotes exhibit suppressed serum LH levels relative to control females (17.4 +/- 3.0 ng/ml vs 57.8 +/- 17.7 ng/ml, respectively), as shown by RIA analysis

increased circulating interleukin-6 level ( J:219024 )

• increase in the mean serum IL-6 concentration from 10 to 50 weeks of age

increased circulating tumor necrosis factor level ( J:219024 )

• increase in serum TNF-alpha levels from 10 weeks of age

cellular

abnormal mitochondrial morphology ( J:219024 )

• mitochondrial swelling, disorientation, shortening, and disorganization of cristae are seen in 80% of 50 week old mice compared to 40% of wild-type mice at this age

disorganized mitochondrial cristae ( J:219024 )

• in 50 week old mice

dilated mitochondrion ( J:219024 )

• in 50 week old mice

oxidative stress ( J:219024 )

• mice exhibit changes in oxidative stress markers in the meibomian glands

immune system

increased circulating interleukin-6 level ( J:219024 )

• increase in the mean serum IL-6 concentration from 10 to 50 weeks of age

increased circulating tumor necrosis factor level ( J:219024 )

• increase in serum TNF-alpha levels from 10 weeks of age

increased interleukin-6 secretion ( J:219024 )

• increase in tear IL-6 concentration from 10 to 50 weeks of age

increased tumor necrosis factor secretion ( J:219024 )

• increase in mean tear TNF-alpha concentration from 10 to 50 weeks of age

blepharitis ( J:219024 )

• eyelid inflammation

• mice exhibit changes in tear, serum and eye lid tissue inflammatory markers

Meibomian gland inflammation ( J:219024 )

• increase in periglandular inflammatory infiltrates from 10 to 50 weeks of age

integument

abnormal Meibomian gland morphology ( J:219024 )

• increase in periglandular fibrosis from 10 to 50 weeks of age

abnormal Meibomian gland acinus morphology ( J:219024 )

• decrease in meibomian gland glandular acinar density from 10 to 50 weeks of age

• accumulation of large lipid droplets in the acinar units of meibomian glands of 50 weeks of age; lipid droplets become larger in size and increase in number from 10 to 50 weeks of age

abnormal Meibomian gland physiology ( J:219024 )

• increase in apoptosis within the meibomian glands at 50 weeks of age

Meibomian gland inflammation ( J:219024 )

• increase in periglandular inflammatory infiltrates from 10 to 50 weeks of age

vision/eye

abnormal Meibomian gland morphology ( J:219024 )

• increase in periglandular fibrosis from 10 to 50 weeks of age

abnormal Meibomian gland acinus morphology ( J:219024 )

• decrease in meibomian gland glandular acinar density from 10 to 50 weeks of age

• accumulation of large lipid droplets in the acinar units of meibomian glands of 50 weeks of age; lipid droplets become larger in size and increase in number from 10 to 50 weeks of age

blepharitis ( J:219024 )

• eyelid inflammation

• mice exhibit changes in tear, serum and eye lid tissue inflammatory markers

Meibomian gland inflammation ( J:219024 )

• increase in periglandular inflammatory infiltrates from 10 to 50 weeks of age

abnormal cornea epithelium morphology ( J:219024 )

• mean corneal vital staining score is worse at 10 and 50 weeks of age indicating ocular surface epithelial cell damage

abnormal tear production ( J:219024 )

• lower tear break up time is seen at 50 weeks of age compared to wild-type mice indicating decreased tear stability

decreased tear production ( J:219024 )

• mean weight adjusted aqueous tear production is lower at 10 and 50 weeks of age and mice show a significant decrease in tear quantity from 10 to 50 weeks of age

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
dry eye syndrome		DOID:10140		J:219024

Genotype
MGI:6382796

hm3

• Allelic Composition: Sod1^tm1Leb/Sod1^tm1Leb
• Genetic Background: involves: 129S7/SvEvBrd-Hprt^b-m2 * C57BL/6

vision/eye

thin retina inner nuclear layer ( J:134267 )

• progressive age-related thinning from age 30 weeks

disorganized retina inner nuclear layer ( J:134267 )

• swollen nuclei, vacuolized cytoplasm and disrupted plasma and nuclear membranes in 15-month-old senescent mice

thin retina outer nuclear layer ( J:134267 )

• progressive age-related thinning from age 30 weeks

disorganized retina outer nuclear layer ( J:134267 )

• decreased density, swollen cell bodies and damaged mitochondria in 15-month-old senescent mice

decreased a-wave amplitude ( J:134267 )

• with scotopic and photopic ERG at age 42 and 81 weeks

decreased b-wave amplitude ( J:134267 )

• with scotopic and photopic ERG at age 42 and 81 weeks

Genotype
MGI:3580496

ht4

• Allelic Composition: Sod1^tm1Leb/Sod1⁺
• Genetic Background: B6;129S-Sod1^tm1Leb/J

nervous system

cochlear ganglion degeneration ( J:102419 )

• contrary to previous findings, heterozygotes display no significant differences in ABR thresholds relative to wild-type mice at any age or any frequency tested

• no degenerative changes are noted in the heterozygous stria vascularis even at 18 months of age

• however, unlike wild-type mice, aging heterozygotes show a decrease in ganglion cell density at 15 months