Analysis Tools
mortality/aging
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• approximately 93% of homozygous null mutants died shortly after birth due to respiratory failure with collapsed pulmonary alveoli
(J:52575)
• the remaining 7% of homozygous null mice survived the perinatal period but developed dwarfism
(J:52575)
• contrary to original findings describing a 7% survival rate for homozygous null mice with dwarfism and severe chondrodysplasia, a subsequent study involving genetic rescue of the perinatal lethality and chondrodysplasia phenotypes reported no surviving homozygous mutant mice
(J:85802)
• in homozygous null mice, cartilage-specific transgene expression completely abolished the perinatal mortality and, depending on the level of transgene expression, resulted in partial to complete rescue of the ensuing skeletal abnormalities; perinatal lethality was, at least, partly attributed to insufficient cartilage function of the upper respiratory tract
(J:85802)
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craniofacial
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• the antero-posterior axis of the skull base was shortened with underdeveloped ossification of the ethmoid, body of sphenoid and base of occipital bone
• in contrast, the frontal and parietal bones and occipital squama displayed normal formation and mineralization
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• the antero-posterior axis of the skull base was shortened
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• the mutant mandibula was small, probably due to an underdeveloped Meckel's cartilage
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• the malleus, incus and stapes of homozygous null newborns appeared underdeveloped
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short snout
(
J:52575
)
growth/size/body
short snout
(
J:52575
)
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• homozygous null survivors developed progressive dwarfism
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hearing/vestibular/ear
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• the malleus, incus and stapes of homozygous null newborns appeared underdeveloped
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limbs/digits/tail
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• both bones and cartilage were present; however, newborn mice stained with alcian blue/alizarin red displayed shortened fore- and hind-limbs
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skeleton
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• homozygous null bone displayed thickened collar, cortex and trabeculae, suggesting that bone formed mainly through membranous ossification
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• the antero-posterior axis of the skull base was shortened with underdeveloped ossification of the ethmoid, body of sphenoid and base of occipital bone
• in contrast, the frontal and parietal bones and occipital squama displayed normal formation and mineralization
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• the antero-posterior axis of the skull base was shortened
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• the mutant mandibula was small, probably due to an underdeveloped Meckel's cartilage
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• the malleus, incus and stapes of homozygous null newborns appeared underdeveloped
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• both bones and cartilage were present; however, newborn mice stained with alcian blue/alizarin red displayed shortened fore- and hind-limbs
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• homozygous null mice exhibited a small epiphysis of long bones
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• homozygous null mice exhibited a slightly flared metaphysis of long bones
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• the lengths of the humerus, radius, femur and tibia of newborn mutant mice were approximately 77%, 56%, 71% and 55% that of wild-type, respectively
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short scapula
(
J:52575
)
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• the length of the scapulas of newborn mutant mice was approximately 58% of controls
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• homozygous null mice exhibited flattened vertebrae
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• the skeletons of newborn mutants exhibited reduced cartilage and delayed endochondral ossification
• at E14.5, the mutant cartilage exhibited reduced numbers and sizes of hypertrophic chondrocytes, suggesting that the mutation primarily affects differentiation from prehypertrophic to hypertrophic chondrocytes
• cell proliferation remained unaffected, as determined by BrdU incorporation
• reduced safranin-o staining in mutant cartilage indicated a reduction in glycosaminoglycan deposition; the level of aggrecan was significantly reduced in the hypertrophic zone of mutant cartilage
• the amount of type II collagen per dry weight of cartilage was similar in homozygous null and wild-type mice, although mutant cartilage was reduced in size
• radiographs of four-week-old mutant mice revealed the presence of a domed skull, small epiphyses and flared metaphysis of tibia and flat vertebrae, all characteristic of spondyloepiphyseal dysplasia
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• in mutant skeletons, the proliferative and hypertrophic zones appeared less distinct, and the columns of chondrocytes in the growth plate were disorganized with little bone replacement
• similar to limb cartilage, chondrocytes of the vertebral bodies were also disorganized; the nucleus porposus was reduced and the annulus fibrosus appeared less distinct
• the number of hypertrophic chondrocytes forming vertebral bodies was decreased relative to wild-type, although the size of the vertebrae was similar to wild-type
• in situ hybridization revealed reduced Indian hedgehog expression in prehypertrophic chondrocytes, reflecting a decrease in the number of prehypertrophic chondrocytes in mutant cartilage; in addition, TUNEL analysis indicated that apoptosis of hypertrophic chondrocytes, a critical step for endochondral ossification, was inhibited in mutant cartilage
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| spondyloepiphyseal dysplasia congenita | DOID:14789 |
OMIM:183900 |
J:52575 | |
