Phenotypes associated with this allele

• Allele Symbol: Tnfrsf11b^tm1Khs
• Allele Name: targeted mutation 1, Kanji Higashio
• Allele ID: MGI:2181227
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Tnfrsf11b^tm1Khs/Tnfrsf11b^tm1Khs	B6.129P2-Tnfrsf11b^tm1Khs	MGI:3698052
hm2	Tnfrsf11b^tm1Khs/Tnfrsf11b^tm1Khs	involves: 129P2/OlaHsd * C57BL/6	MGI:3653631
cx3	Kl^kl/Kl^kl Tnfrsf11b^tm1Khs/Tnfrsf11b^+	involves: 129P2/OlaHsd * C3H * C57BL/6	MGI:3653639

Genotype
MGI:3698052

hm1

• Allelic Composition: Tnfrsf11b^tm1Khs/Tnfrsf11b^tm1Khs
• Genetic Background: B6.129P2-Tnfrsf11b^tm1Khs

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

hearing/vestibular/ear

abnormal inner ear morphology ( J:117756 )

otosclerosis ( J:117756 )

• the active remodeling process resembles otosclerosis seen in human temporal bones

• however, no histological evidence of stapes fixation is observed

abnormal otic capsule morphology ( J:117756 )

• homozygotes display abnormal bone remodeling within the otic capsule with multiple foci showing osteoclastic bone resorption and formation of new bone, not observed in C57BL/6 control mice

• hypercellular areas contain multinucleated osteoclasts as well as numerous osteoblasts and blood vessels

• in hypercellular areas, the bone is sometimes abnormally thick

• in some areas, bone resorption traverses the entire width of the otic capsule

• in some cases, the bone is eroded so that hypercellular areas come in contact with the spiral ligament, resulting in hyalinization

• in some areas, bone resoption results in cavitary lesions, communicating with the middle ear air space or inner ear fluid

• otic capsule remodeling is more severe in older mutants and progressively worsens over time

abnormal middle ear morphology ( J:117756 )

• in regions of bone remodeling, the overlying middle ear mucosa is abnormally thickened

abnormal malleus morphology ( J:117756 )

• the malleus exhibits abnormal bone remodeling with areas of hypercelularity

abnormal stapes footplate morphology ( J:117756 )

• in regions of bone remodeling, the stapes footplate appears eroded

increased or absent threshold for auditory brainstem response ( J:117756 )

• at 8 weeks, homozygotes display high-frequency ABR threshold elevations relative to age-matched C57BL/6 control mice, while low- to midfrequency responses are normal for both groups

• by 21 weeks, homozygotes additionally display low- and midfrequency ABR threshold elevations, not observed in age-matched C57BL/6 control mice

increased or absent distortion product otoacoustic emission threshold ( J:117756 )

• at 8 weeks, homozygotes exhibit increased DPOAE thresholds to near equipment limits at both low and high frequencies

absent distortion product otoacoustic emissions ( J:117756 )

• by 21 weeks, DPOAEs are largely absent or near equipment limits

increased susceptibility to age-related hearing loss ( J:117756 )

• homozygotes exhibit hearing loss that progressively involves mid and lower frequencies in addition to high frequences with advancing age

deafness ( J:117756 )

• homozygotes exhibit a progressive and severe hearing loss that is first apparent in high frequencies and subsequently involves mid and lower frequencies at later ages

skeleton

otosclerosis ( J:117756 )

• the active remodeling process resembles otosclerosis seen in human temporal bones

• however, no histological evidence of stapes fixation is observed

abnormal malleus morphology ( J:117756 )

• the malleus exhibits abnormal bone remodeling with areas of hypercelularity

abnormal stapes footplate morphology ( J:117756 )

• in regions of bone remodeling, the stapes footplate appears eroded

osteoporosis ( J:117756 )

abnormal bone remodeling ( J:117756 )

• homozygotes display abnormal bone remodeling within the otic capsule with multiple foci showing osteoclastic bone resorption and formation of new bone, not observed in C57BL/6 control mice

• middle ear ossicles exhibit remodeling with abnormal areas of hypercelularity in the malleus and erosion of the stapes footplate

• abnormal bone remodeling is associated with increased bone vascularization, esp. at the base of cochlea where the bone is thickest

craniofacial

otosclerosis ( J:117756 )

• the active remodeling process resembles otosclerosis seen in human temporal bones

• however, no histological evidence of stapes fixation is observed

abnormal malleus morphology ( J:117756 )

• the malleus exhibits abnormal bone remodeling with areas of hypercelularity

abnormal stapes footplate morphology ( J:117756 )

• in regions of bone remodeling, the stapes footplate appears eroded

Genotype
MGI:3653631

hm2

• Allelic Composition: Tnfrsf11b^tm1Khs/Tnfrsf11b^tm1Khs
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6

mortality/aging

postnatal lethality, incomplete penetrance ( J:48325 )

• at weaning only 18.7% are homozygous rather than the expected 25%

growth/size/body

postnatal growth retardation ( J:48325 )

skeleton

abnormal middle ear ossicle morphology ( J:111153 )

• increase in tartrate-resistant acid phosphatase activity (marker of osteoclasts and resorption lacunae) and thinning are seen in all three middle ear ossicles

abnormal incus body morphology ( J:111153 )

• thinning, particularly of the incus body

abnormal malleus morphology ( J:111153 )

• thinning, particularly in the manubrium and processus brevis

• malleal cortical thickness is significantly reduced

abnormal stapes morphology ( J:111153 )

• thinning, particularly of the arch

abnormal stapes annular ligament morphology ( J:111153 )

• the ligament between the stapedial footplate and the otic capsule is replaced with a bony tissue resulting in fusion of the stapes to the otic capsule

abnormal stapes footplate morphology ( J:111153 )

• the stapes footplate is thinner and broader at the periphery

abnormal bone structure ( J:111153 )

increased osteoclast cell number ( J:80503 )

• increased numbers in the metaphyseal region

decreased bone mineral density ( J:48325 , J:111153 )

• reduced radiodensity especially in the tail and the distal portions of the femur and tibia (J:48325)

• bone mineral density is reduced by 27.5% compared to wild-type (J:48325)

• tibial cortical bone mineral density is reduced (J:111153)

abnormal trabecular bone morphology ( J:48325 )

• absent from the femur

• at 8 weeks of age trabecular bone is poorly extended

osteoporosis ( J:48325 )

abnormal skeleton development ( J:111153 )

abnormal osteoclast differentiation ( J:48325 , J:111153 )

• at 8 weeks of age, osteoclasts are seen throughout the trabecular and cortical bone, including in the chondro-osseous junction and the intertrabecular areas of the trabecular bone (J:48325)

• at 13 weeks of age, osteoclasts are seen in the growth plate (J:48325)

• increase in the number of tartrate-resistant acid phosphatase positive multinucleated cells in the mallei (J:111153)

abnormal long bone epiphyseal plate morphology ( J:48325 )

• at 8 and 13 weeks, but not 5 weeks, progressive destruction of the growth plate is seen

abnormal skeleton physiology ( J:111153 )

abnormal osteoclast physiology ( J:111153 )

• increase in tartrate-resistant acid phosphatase activity (marker of osteoclasts and resorption lacunae) in all three middle ear ossicles and in the otic capsule

fragile skeleton ( J:48325 )

• spontaneous fractures of the tibia or femur

• at 8 weeks of age trabecular bone is poorly extended

hearing/vestibular/ear

abnormal inner ear morphology ( J:111153 )

• the ligament between the stapedial footplate and the otic capsule is replaced with a bony tissue resulting in fusion of the stapes to the otic capsule

abnormal middle ear morphology ( J:111153 )

• junction between the stapes and the oval window of the cochlea is tighter

abnormal middle ear ossicle morphology ( J:111153 )

• increase in tartrate-resistant acid phosphatase activity (marker of osteoclasts and resorption lacunae) and thinning are seen in all three middle ear ossicles

abnormal incus body morphology ( J:111153 )

• thinning, particularly of the incus body

abnormal malleus morphology ( J:111153 )

• thinning, particularly in the manubrium and processus brevis

• malleal cortical thickness is significantly reduced

abnormal stapes morphology ( J:111153 )

• thinning, particularly of the arch

abnormal stapes annular ligament morphology ( J:111153 )

• the ligament between the stapedial footplate and the otic capsule is replaced with a bony tissue resulting in fusion of the stapes to the otic capsule

abnormal stapes footplate morphology ( J:111153 )

• the stapes footplate is thinner and broader at the periphery

increased or absent threshold for auditory brainstem response ( J:111153 )

• starting at 10 weeks of age, progressive increase in auditory brain-stem response thresholds is seen; however, no difference is seen at 6 weeks of age

• at 15 weeks of age thresholds are 20 dB higher at 20 kHz compared to wild-type mice

craniofacial

abnormal middle ear ossicle morphology ( J:111153 )

• increase in tartrate-resistant acid phosphatase activity (marker of osteoclasts and resorption lacunae) and thinning are seen in all three middle ear ossicles

abnormal incus body morphology ( J:111153 )

• thinning, particularly of the incus body

abnormal malleus morphology ( J:111153 )

• thinning, particularly in the manubrium and processus brevis

• malleal cortical thickness is significantly reduced

abnormal stapes morphology ( J:111153 )

• thinning, particularly of the arch

abnormal stapes annular ligament morphology ( J:111153 )

• the ligament between the stapedial footplate and the otic capsule is replaced with a bony tissue resulting in fusion of the stapes to the otic capsule

abnormal stapes footplate morphology ( J:111153 )

• the stapes footplate is thinner and broader at the periphery

hematopoietic system

abnormal osteoclast differentiation ( J:48325 , J:111153 )

• at 8 weeks of age, osteoclasts are seen throughout the trabecular and cortical bone, including in the chondro-osseous junction and the intertrabecular areas of the trabecular bone (J:48325)

• at 13 weeks of age, osteoclasts are seen in the growth plate (J:48325)

• increase in the number of tartrate-resistant acid phosphatase positive multinucleated cells in the mallei (J:111153)

increased osteoclast cell number ( J:80503 )

• increased numbers in the metaphyseal region

abnormal osteoclast physiology ( J:111153 )

• increase in tartrate-resistant acid phosphatase activity (marker of osteoclasts and resorption lacunae) in all three middle ear ossicles and in the otic capsule

immune system

abnormal osteoclast differentiation ( J:48325 , J:111153 )

• at 8 weeks of age, osteoclasts are seen throughout the trabecular and cortical bone, including in the chondro-osseous junction and the intertrabecular areas of the trabecular bone (J:48325)

• at 13 weeks of age, osteoclasts are seen in the growth plate (J:48325)

• increase in the number of tartrate-resistant acid phosphatase positive multinucleated cells in the mallei (J:111153)

increased osteoclast cell number ( J:80503 )

• increased numbers in the metaphyseal region

abnormal osteoclast physiology ( J:111153 )

• increase in tartrate-resistant acid phosphatase activity (marker of osteoclasts and resorption lacunae) in all three middle ear ossicles and in the otic capsule

cellular

abnormal osteoclast differentiation ( J:48325 , J:111153 )

• at 8 weeks of age, osteoclasts are seen throughout the trabecular and cortical bone, including in the chondro-osseous junction and the intertrabecular areas of the trabecular bone (J:48325)

• at 13 weeks of age, osteoclasts are seen in the growth plate (J:48325)

• increase in the number of tartrate-resistant acid phosphatase positive multinucleated cells in the mallei (J:111153)

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
osteoporosis		DOID:11476	OMIM:166710	J:48325

Genotype
MGI:3653639

cx3

• Allelic Composition: Kl^kl/Kl^kl; Tnfrsf11b^tm1Khs/Tnfrsf11b⁺
• Genetic Background: involves: 129P2/OlaHsd * C3H * C57BL/6

skeleton

short femur ( J:80503 )

• femur length is shorter than in mice homozygous for Kl only; however osteopetrotic changes in the bone are reduced and the number of osteoclasts is similar to wild-type

growth/size/body

decreased body weight ( J:80503 )

• similar to mice homozygous for Kl mutation only

immune system

decreased B cell number ( J:80503 )

• similar to mice homozygous for Kl mutation only

limbs/digits/tail

short femur ( J:80503 )

• femur length is shorter than in mice homozygous for Kl only; however osteopetrotic changes in the bone are reduced and the number of osteoclasts is similar to wild-type

hematopoietic system

decreased B cell number ( J:80503 )

• similar to mice homozygous for Kl mutation only