Mouse Genome Informatics
hm1
    Fgfr3tm1Dor/Fgfr3tm1Dor
CBA/Ca.129S6(B6)-Fgfr3tm1Dor
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hearing/vestibular/ear
• at P0, homozygotes display failure of pillar cell differentiation, as shown by lack of separation between inner and outer hair cells
• inner pillar cells never develop while outer pillar cell differentiation is stalled
• homozygotes exhibit an expansion of the sensory epithelium to include one extra OHC row and accompanying Dieters cells
• at 4 weeks, homozygotes lack a well-defined separation between IHCs and OHCs
• Background Sensitivity: no extra OHC row is noted on a mixed 129S6/SvEvTac x C57BL/6 genetic background
• on a CBA/CaJ congenic background, E17.5 homozygotes on a with an extra row of Dieters cells display an extra fourth row of OHCs in the apical two thirds of the cochlea
• an extra OHC row occurs precisely at the transition from 3 to 4 rows of Dieters cells; however, OHC stereociliary bundle formation and overall cochlear length remain normal
• homozygotes display an additional row of Dieters cells (i.e. 4 rows instead of 3) in the apical two thirds of the cochlea
• homozygotes show loss of one row of pillar cells throughout the cochlea
• adult homozygotes show a complete lack of tunnel formation
• homozygotes display a 50-60 dB threshold shift across all frequencies
• homozygotes display a severe hearing loss due to pillar defects

nervous system
• at 4 weeks, homozygotes lack a well-defined separation between IHCs and OHCs
• Background Sensitivity: no extra OHC row is noted on a mixed 129S6/SvEvTac x C57BL/6 genetic background
• on a CBA/CaJ congenic background, E17.5 homozygotes on a with an extra row of Dieters cells display an extra fourth row of OHCs in the apical two thirds of the cochlea
• an extra OHC row occurs precisely at the transition from 3 to 4 rows of Dieters cells; however, OHC stereociliary bundle formation and overall cochlear length remain normal

cellular
• at P0, homozygotes display failure of pillar cell differentiation, as shown by lack of separation between inner and outer hair cells
• inner pillar cells never develop while outer pillar cell differentiation is stalled


Mouse Genome Informatics
hm2
    Fgfr3tm1Dor/Fgfr3tm1Dor
involves: 129S6/SvEvTac
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
skeleton
• humerus length of neonates is 3.43 mm versus 2.8 mm in wild-type neonates
• radius length of neonates is 3.8 mm versus 3.04 mm in wild-type neonates
• ulna is longer in neonates than in controls
• femur length of neonates is 2.78 mm versus 2.46 mm in wild-type neonates
• there is also a slight but significant increase in proliferating cells of the epiphyses (16.5% versus 13.03%)
• depth of both type II and type X collagen immunoreactive cells is increased in the cartilage of the tibial epiphysis of neonates
• there is a disproportionate increase in the depth of type X positive cells that demarcate the hypertrophic zone
• the axial skeleton is elongated in neonates compared to controls

nervous system
N
• mutants do not show defects in brain morphology and development (hindbrain patterning, boundary development or neurotransmitter system) (J:118802)
• mice do not display any defects in motor neuron patterning (J:122940)

limbs/digits/tail
• humerus length of neonates is 3.43 mm versus 2.8 mm in wild-type neonates
• radius length of neonates is 3.8 mm versus 3.04 mm in wild-type neonates
• ulna is longer in neonates than in controls
• femur length of neonates is 2.78 mm versus 2.46 mm in wild-type neonates


Mouse Genome Informatics
hm3
    Fgfr3tm1Dor/Fgfr3tm1Dor
involves: 129S6/SvEvTac * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• 48% die between birth and 21 days of age
• mice die at various ages between 1 day and 8 months of age

growth/size
• weight ranges from 17-93% of that of controls

hearing/vestibular/ear
• adult cochleas resemble those of normal newborn mice
• the blood vessel below the basilar membrane is patent and numerous mesothelial cells are present below the basilar membrane
• reduced innervation of outer hair cells
• as expected, homozygotes exhibit one row of Deiters' cells beneath each of the 3-4 rows of OHCs
• however, homozygotes also have two rows of "Deiters'-like cells", probably due to failure of these cells to develop into pillar cells
• no recognizable inner and outer pillar cells between 15 days and 7 months of age
• at 3 weeks to 6 months, homozygotes show no auditory brainstem responses at 100 dB SPL, indicating profound deafness

skeleton
• overgrowth of the humerus in 6 month or older mice
• 75% of 7 week or older mice exhibit increased curvature of the humerus
• increased curvature of the femur in 7 week or older mice
• femurs at 4.5 months of age or older are 6-27% longer than controls
• growth plates contain more hypertrophic chondrocytes than controls
• consistent increase in the size of hypertrophic zones
• height of the proximal tibial hypertrophic zone at E18.5 and P1 is increased 33-50%
• growth plates of long bones are longer at 3 weeks of age
• acellular bands in growth plates are narrower and less numerous than in controls
• ribs are abnormally shaped, resulting in a reduction of thoracic cavity volume
• primarily in the cervical and upper thoracic spine
• first observed at 1 week after birth and develops in all mice by several months of age
• severe scoliosis, primarily in the cervical and upper thoracic spine
• overgrowth of the lumbar vertebral bodies in 6 month old mice

behavior/neurological
• several hours after birth, have smaller milk spots, indicating poor nursing

limbs/digits/tail
• overgrowth of the humerus in 6 month or older mice
• 75% of 7 week or older mice exhibit increased curvature of the humerus
• increased curvature of the femur in 7 week or older mice
• femurs at 4.5 months of age or older are 6-27% longer than controls
• tail kinks or bends are first observed at P1 and develop in 72% of mice

nervous system
• reduced innervation of outer hair cells

cellular

Mouse Models of Human Disease
OMIM IDRef(s)
NOT Achondroplasia; ACH 100800 J:32991
NOT Hypochondroplasia; HCH 146000 J:32991


Mouse Genome Informatics
cx4
    Fgfr3tm1Dor/Fgfr3tm1Dor
Pthlhtm1Fbe/Pthlhtm1Fbe

involves: 129S1/Sv * 129S6/SvEvTac * 129X1/SvJ
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• neonatal lethality occurs to these mice

skeleton
• humerus length of neonates is 2.10 mm versus 2.80 mm in wild-type neonates
• radius length of neonates is 2.30 mm versus 3.04 mm in wild-type neonates
• is observed in neonates compared to controls
• femur length of neonates is 2.14 mm versus 2.46 mm in wild-type neonates
• there is a significant decrease in proliferating cells of the epiphyses (8.74% versus 13.03%)
• larger, irregularly shaped cells are dispersed among the normal, regular shaped hypertrophic cells
• mineral deposits are only observed in the lowermost zones of hyprertrophic cells instead of throughout the hypertrophic zone as is seen in wild-type
• while the epiphyseal cartilage is reduced compared to wild-type, there is a disproportionate increase in the depth of type X positive cells that demarcate the hypertrophic zone
• the total epiphyseal cartilage is considerably reduced compared to controls
• the axial skeleton is shortened in neonates compared to controls
• is observed in these mice

limbs/digits/tail
• humerus length of neonates is 2.10 mm versus 2.80 mm in wild-type neonates
• radius length of neonates is 2.30 mm versus 3.04 mm in wild-type neonates
• is observed in neonates compared to controls
• femur length of neonates is 2.14 mm versus 2.46 mm in wild-type neonates
• is observed in these mice

craniofacial
• is observed in these mice


Mouse Genome Informatics
cx5
    Fgfr3tm1Dor/Fgfr3tm1Dor
Tg(SFTPC-rtTA)5Jaw/0
Tg(tetO-Fgf9,-EGFP)#Dor/0

involves: 129S6/SvEvTac * C57BL/6J * FVB
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
tumorigenesis
• at 1 week or 1 month of induction with doxycycline, mutants do not exhibit formation of lung tumors and lung histology remains normal