Mouse Genome Informatics
hm
    Hapln1tm1Nid/Hapln1tm1Nid
involves: 129S1/Sv * 129X1/SvJ
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       
mortality/aging
• 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)

craniofacial
• 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
• the malleus, incus and stapes of homozygous null newborns appeared underdeveloped
• the mutant mandibula was small, probably due to an underdeveloped Meckel's cartilage
• newborn homozygous null mice had a flat face

growth/size/body
• newborn homozygous null mice had a flat face
• homozygous null survivors developed progressive dwarfism

hearing/vestibular/ear
• the malleus, incus and stapes of homozygous null newborns appeared underdeveloped

limbs/digits/tail
• both bones and cartilage were present; however, newborn mice stained with alcian blue/alizarin red displayed shortened fore- and hind-limbs

skeleton
• homozygous null bone displayed thickened collar, cortex and trabeculae, suggesting that bone formed mainly through membranous ossification
• 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
• the malleus, incus and stapes of homozygous null newborns appeared underdeveloped
• the mutant mandibula was small, probably due to an underdeveloped Meckel's cartilage
• both bones and cartilage were present; however, newborn mice stained with alcian blue/alizarin red displayed shortened fore- and hind-limbs
• homozygous null mice exhibited a small epiphysis of long bones
• homozygous null mice exhibited a slightly flared metaphysis of long bones
• 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
• the length of the scapulas of newborn mutant mice was approximately 58% of controls
• homozygous null survivors developed lordosis of the cervical spine
• homozygous null mice exhibited flattened vertebrae
• 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
• 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

Mouse Models of Human Disease
OMIM IDRef(s)
Spondyloepiphyseal Dysplasia Congenita; SEDC 183900 J:52575