homeostasis/metabolism phenotype

• suppressed circulating follicle stimulating hormone level
  • 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
  (MGI Ref ID J:64299)

• increased circulating interleukin-6 level
  • increase in the mean serum IL-6 concentration from 10 to 50 weeks of age
  (MGI Ref ID J:219024)

• decreased circulating luteinizing hormone level
  • 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
  (MGI Ref ID J:64299)

• increased circulating tumor necrosis factor level
  • increase in serum TNF-alpha levels from 10 weeks of age
  (MGI Ref ID J:219024)

immune system phenotype

• blepharitis
  • eyelid inflammation
  (MGI Ref ID J:219024)
  • mice exhibit changes in tear, serum and eye lid tissue inflammatory markers
  (MGI Ref ID J:219024)

• increased circulating tumor necrosis factor level
  • increase in serum TNF-alpha levels from 10 weeks of age
  (MGI Ref ID J:219024)

• increased tumor necrosis factor secretion
  • increase in mean tear TNF-alpha concentration from 10 to 50 weeks of age
  (MGI Ref ID J:219024)

• Meibomian gland inflammation
  • increase in periglandular inflammatory infiltrates from 10 to 50 weeks of age
  (MGI Ref ID J:219024)

• increased circulating interleukin-6 level
  • increase in the mean serum IL-6 concentration from 10 to 50 weeks of age
  (MGI Ref ID J:219024)

• increased interleukin-6 secretion
  • increase in tear IL-6 concentration from 10 to 50 weeks of age
  (MGI Ref ID J:219024)

cellular phenotype

• dilated mitochondria
  • in 50 week old mice
  (MGI Ref ID J:219024)

• oxidative stress
  • mice exhibit changes in oxidative stress markers in the meibomian glands
  (MGI Ref ID J:219024)

• abnormal mitochondrial morphology
  • 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
  (MGI Ref ID J:219024)

• disorganized mitochondrial cristae
  • in 50 week old mice
  (MGI Ref ID J:219024)

integument phenotype

• abnormal Meibomian gland acinus morphology
  • 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
  (MGI Ref ID J:219024)
  • decrease in meibomian gland glandular acinar density from 10 to 50 weeks of age
  (MGI Ref ID J:219024)

• abnormal Meibomian gland morphology
  • increase in periglandular fibrosis from 10 to 50 weeks of age
  (MGI Ref ID J:219024)

• Meibomian gland inflammation
  • increase in periglandular inflammatory infiltrates from 10 to 50 weeks of age
  (MGI Ref ID J:219024)

• abnormal Meibomian gland physiology
  • increase in apoptosis within the meibomian glands at 50 weeks of age
  (MGI Ref ID J:219024)

reproductive system phenotype

• decreased litter size
  • 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)
  (MGI Ref ID J:64299)

• decreased mature ovarian follicle number
  • while normal-appearing primary follicles and some small antral follicles are present, only a few large antral follicles and corpora lutea are observed
  (MGI Ref ID J:64299)

• reduced female fertility
  • female homozygotes survive to adulthood and appear to show normal sexual differentiation but are subfertile
  (MGI Ref ID J:64299)
  • Normal - however, mutant and control females were shown to produce a similar number of eggs upon pharmacological superovulation
  (MGI Ref ID J:64299)
  • Normal - in contrast to females, male homozygotes are fertile with normal testicular morphology
  (MGI Ref ID J:64299)
  • 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
  (MGI Ref ID J:64299)

• small ovary
  • homozygous mutant ovaries are often smaller than wild-type ovaries
  (MGI Ref ID J:64299)

• abnormal ovary morphology
  • at 12 weeks of age, increased stromal cell proliferation is noted in the center of the mutant ovary
  (MGI Ref ID J:64299)

• female infertility
  • 5 of 16 female homozygotes failed to become pregnant over a 2-6 month period
  (MGI Ref ID J:64299)

• decreased corpora lutea number
  (MGI Ref ID J:64299)

• impaired ovarian folliculogenesis
  • at 6-12 weeks of age, female homozygotes show limited follicular development beyond the early antral follicle stage
  (MGI Ref ID J:64299)

vision/eye phenotype

• abnormal tear production
  • lower tear break up time is seen at 50 weeks of age compared to wild-type mice indicating decreased tear stability
  (MGI Ref ID J:219024)

• abnormal Meibomian gland acinus morphology
  • decrease in meibomian gland glandular acinar density from 10 to 50 weeks of age
  (MGI Ref ID J:219024)
  • 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
  (MGI Ref ID J:219024)

• abnormal Meibomian gland morphology
  • increase in periglandular fibrosis from 10 to 50 weeks of age
  (MGI Ref ID J:219024)

• blepharitis
  • mice exhibit changes in tear, serum and eye lid tissue inflammatory markers
  (MGI Ref ID J:219024)
  • eyelid inflammation
  (MGI Ref ID J:219024)

• decreased tear production
  • 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
  (MGI Ref ID J:219024)

• abnormal corneal epithelium morphology
  • mean corneal vital staining score is worse at 10 and 50 weeks of age indicating ocular surface epithelial cell damage
  (MGI Ref ID J:219024)

• Meibomian gland inflammation
  • increase in periglandular inflammatory infiltrates from 10 to 50 weeks of age
  (MGI Ref ID J:219024)

endocrine/exocrine gland phenotype

• abnormal Meibomian gland acinus morphology
  • 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
  (MGI Ref ID J:219024)
  • decrease in meibomian gland glandular acinar density from 10 to 50 weeks of age
  (MGI Ref ID J:219024)

• abnormal Meibomian gland morphology
  • increase in periglandular fibrosis from 10 to 50 weeks of age
  (MGI Ref ID J:219024)

• impaired ovarian folliculogenesis
  • at 6-12 weeks of age, female homozygotes show limited follicular development beyond the early antral follicle stage
  (MGI Ref ID J:64299)

• small ovary
  • homozygous mutant ovaries are often smaller than wild-type ovaries
  (MGI Ref ID J:64299)

• decreased corpora lutea number
  (MGI Ref ID J:64299)

• decreased mature ovarian follicle number
  • while normal-appearing primary follicles and some small antral follicles are present, only a few large antral follicles and corpora lutea are observed
  (MGI Ref ID J:64299)

• Meibomian gland inflammation
  • increase in periglandular inflammatory infiltrates from 10 to 50 weeks of age
  (MGI Ref ID J:219024)

• abnormal Meibomian gland physiology
  • increase in apoptosis within the meibomian glands at 50 weeks of age
  (MGI Ref ID J:219024)

• abnormal ovary morphology
  • at 12 weeks of age, increased stromal cell proliferation is noted in the center of the mutant ovary
  (MGI Ref ID J:64299)

vision/eye phenotype

• disorganized retinal outer nuclear layer
  • decreased density, swollen cell bodies and damaged mitochondria in 15-month-old senescent mice
  (MGI Ref ID J:134267)

• decreased a-wave amplitude
  • with scotopic and photopic ERG at age 42 and 81 weeks
  (MGI Ref ID J:134267)

• decreased b-wave amplitude
  • with scotopic and photopic ERG at age 42 and 81 weeks
  (MGI Ref ID J:134267)

• disorganized retinal inner nuclear layer
  • swollen nuclei, vacuolized cytoplasm and disrupted plasma and nuclear membranes in 15-month-old senescent mice
  (MGI Ref ID J:134267)

• thin retinal inner nuclear layer
  • progressive age-related thinning from age 30 weeks
  (MGI Ref ID J:134267)

• thin retinal outer nuclear layer
  • progressive age-related thinning from age 30 weeks
  (MGI Ref ID J:134267)

vision/eye phenotype

• abnormal eye electrophysiology
  • Normal - however, the intraocular pressure is normal
  (MGI Ref ID 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
  (MGI Ref ID J:181434)

• decreased retinal ganglion cell number
  • Normal - however, photoreceptor cell death is not seen at 24 weeks of age
  (MGI Ref ID 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
  (MGI Ref ID J:181434)

• abnormal retinal ganglion layer morphology
  • level of reactive oxygen species (ROS) in the retinal ganglion cell layer is higher in 24-week old mutants than in wild-type mice
  (MGI Ref ID J:181434)

• abnormal retinal nerve fiber layer morphology
  • 24 week old mutants exhibit thinning of the nerve fiber layer
  (MGI Ref ID J:181434)

hearing/vestibular/ear phenotype

• thin stria vascularis
  • however, no differences in stria vascularis thickness are noted in the apical turn at 7-9 months
  (MGI Ref ID J:102419)
  • at 15 months, homozygotes display a significantly thinner stria vascularis in the apical turn relative to heterozygous or wild-type mice
  (MGI Ref ID J:102419)

• deafness
  • at 12 and 15 months, homozygotes exhibit an earlier and significantly greater hearing loss than age-matched C57BL/6, wild-type or heterozygous mice
  (MGI Ref ID J:102419)

• increased or absent threshold for auditory brainstem response
  • 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
  (MGI Ref ID 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
  (MGI Ref ID J:102419)

nervous system phenotype

• cochlear ganglion degeneration
  • in homozygotes, the magnitude of ganglion cell loss is greater than that of C57BL/6 control mice, esp. above the basal turn
  (MGI Ref ID J:102419)
  • starting at 7-9 months, homozygotes display severe progressive degeneration of spiral ganglion cells in all cochlear turns
  (MGI Ref ID J:102419)

• decreased retinal ganglion cell number
  • Normal - however, photoreceptor cell death is not seen at 24 weeks of age
  (MGI Ref ID 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
  (MGI Ref ID J:181434)

nervous system phenotype

• cochlear ganglion degeneration
  • contrary to previous findings, heterozygotes display no significant differences in ABR thresholds relative to wild-type mice at any age or any frequency tested
  (MGI Ref ID J:102419)
  • however, unlike wild-type mice, aging heterozygotes show a decrease in ganglion cell density at 15 months
  (MGI Ref ID J:102419)
  • no degenerative changes are noted in the heterozygous stria vascularis even at 18 months of age
  (MGI Ref ID J:102419)