Analysis Tools
mortality/aging
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• males are born at a significantly lower frequency than expected
• however, females (which do not express the transgene) are born with normal Mendelian distribution
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• mice exhibit premature deterioration of the skin
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integument
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• tail skin shows atrophy of the sebaceous glands
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• mice develop alopecia of the dorsal skin that becomes more severe with increasing age
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• tail skin shows atrophy of the hair follicles
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• light-exposed areas of tail and ear skin show areas of dysplastic lesions
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• tail skin shows areas of epidermal atrophy
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• ear skin shows dysplastic epidermal hyperplasia with atypical and enlarged nuclei and dermis invasion
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• >78% of mice exhibit skin dryness in areas of dorsal hair loss triggered by exposure to light
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• light-exposed areas of tail and ear skin show areas of hyperplasia
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• in tail skin, the basal cell layer shows accumulation of melanin deposits
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• mice exhibit accumulation of melanin in tail skin
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• mice exhibit acute hyperpigmentation of light-exposed skin areas (tail, paws and ear) relative to wild-type controls
• skin hyperpigmentation is much more severe than that observed in Tg(KRT5-Terf2)POBlas or Tg(KRT5-Terf2)PNBlas transgenic mice
• >30% of mice develop hyperpigmentation that becomes more severe with increasing age
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• UVB-irradiated mice show a significant increase in UV-induced pyrimidine (6-4) photoproducts (6-4 PPs) and of cyclobutyl pyrimidine dimers (CPDs) in skin relative to similarly irradiated wild-type controls
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• light-exposed areas of the skin (tail and ear) show skin dryness, atrophy, hyperpigmentation, hair loss, hyperplastic and dysplastic lesions, and increased incidence of skin tumors with age
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• older mice develop spontaneous tumors in light-exposed areas of the skin, such as the tail
• incidence of spontaneous skin tumors increases with age, with no tumors detected at 6-12 months of age
• at >1 year of age, 50% of mice show keratoacanthomas and squamous cell carcinomas in the tail, with some mice exhibiting multiple tumors
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• at >1 year of age
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• at >1 year of age, some mice exhibit multiple squamous cell carcinomas (SCCs) in the tail skin
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• in culture, primary skin keratinocytes are less viable than those from wild-type controls
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• in tail skin, basal layer keratinocytes show a significant decrease in proliferating (Ki67+) cells
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pigmentation
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• in tail skin, the basal cell layer shows accumulation of melanin deposits
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• mice exhibit accumulation of melanin in tail skin
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• mice exhibit acute hyperpigmentation of light-exposed skin areas (tail, paws and ear) relative to wild-type controls
• skin hyperpigmentation is much more severe than that observed in Tg(KRT5-Terf2)POBlas or Tg(KRT5-Terf2)PNBlas transgenic mice
• >30% of mice develop hyperpigmentation that becomes more severe with increasing age
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cellular
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• in tail skin, basal layer keratinocytes show a significantly higher % of gamma-H2AX-positive nuclei than wild-type cells; 60% of these gamma-H2AX DNA damage foci colocalize with the telomeric protein TERF1, indicating dysfunctional telomeres
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• at 4 months of age, mice have markedly shorter telomeres in tail skin than age-matched wild-type controls
• tail skin (normally exposed to light) shows telomere shortening as early as 20 days after birth, whereas dorsal skin (partially protected from light by hair) shows telomere shortening at later time points
• at 60 days after birth, both tail and dorsal skin show clear telomere shortening, although the effect is more severe in the tail
• Q-FISH analysis of metaphases from primary keratinocytes revealed shorter telomeres, increased frequencies of signal-free ends (telomeres with no TTAGGG signal), and more end-to-end fusions lacking TTAGGG repeats at the fusion point relative to wild-type cells
• adult tail skin keratinocytes show a >50% decrease in the length (loss) of the G-strand overhang relative to wild-type controls
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• in culture, primary keratinocytes are hypersensitive to increasing doses of mitomycin C (MMC), as determined by survival 5 days after MMC treatment
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• UVB-irradiated primary keratinocytes exhibit significantly reduced viability relative to similarly irradiated wild-type keratinocytes
• however, primary keratinocytes show normal sensitivity to gamma irradiation, with no differences in viability relative to similarly irradiated wild-type controls
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• in tail skin, basal layer keratinocytes show a significant decrease in proliferating (Ki67+) cells
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• MMC-treated keratinocytes show a 2-fold increase in complex chromosomal aberrations (breaks, fragments, chromatid crosslinks and tri-radials) relative to MMC-treated wild-type controls, suggesting defective repair of DNA crosslinks
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• Q-FISH analysis of metaphases from primary keratinocytes revealed more complex chromosomal aberrations (chromatid crosslinks, chromosomes with multiple telomeres and interstitial telomeres) relative to wild-type cells
• chromosomal instability is further exacerbated with increasing culture passage
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• MMC-treated keratinocytes show twice as many complex chromosomal breaks and fragments as MMC-treated wild-type keratinocytes
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neoplasm
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• older mice develop spontaneous tumors in light-exposed areas of the skin, such as the tail
• incidence of spontaneous skin tumors increases with age, with no tumors detected at 6-12 months of age
• at >1 year of age, 50% of mice show keratoacanthomas and squamous cell carcinomas in the tail, with some mice exhibiting multiple tumors
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• at >1 year of age
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• at >1 year of age, some mice exhibit multiple squamous cell carcinomas (SCCs) in the tail skin
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• mice develop papillomas and severe skin ulcerations 18 weeks after the start of chronic UVB irradiation treatment, whereas similarly irradiated wild-type cohorts never develop such lesions
• 30 weeks after the start of UVB irradiation treatment, mice develop rapidly growing skin tumors that result in decreased survival, unlike similarly irradiated wild-type controls
• at time of death, chronically irradiated mice show lesions ranging from pretumoral lesions (actinic keratosis, actinic dermatitis, hyperplasia and dysplasia) to different degrees of squamous cell carcinomas (in situ, well differentiated and poorly differentiated) and fibrosarcomas
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homeostasis/metabolism
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• MMC-treated keratinocytes show a 2-fold increase in complex chromosomal aberrations (breaks, fragments, chromatid crosslinks and tri-radials) relative to MMC-treated wild-type controls, suggesting defective repair of DNA crosslinks
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craniofacial
endocrine/exocrine glands
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• tail skin shows atrophy of the sebaceous glands
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growth/size/body
hearing/vestibular/ear
limbs/digits/tail
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• mice exhibit accumulation of melanin in tail skin
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| xeroderma pigmentosum | DOID:0050427 | J:102653 | ||
