Phenotypes associated with this allele

• Allele Symbol: Vdr^tm1Ska
• Allele Name: targeted mutation 1, Shigeaki Kato
• Allele ID: MGI:1859929
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Vdr^tm1Ska/Vdr^tm1Ska	involves: 129 * C57BL/6NCrlj * CBA/JNCrlj	MGI:3664027
hm2	Vdr^tm1Ska/Vdr^tm1Ska	involves: C57BL/6NCrlj * CBA/JNCrlj	MGI:2174799
hm3	Vdr^tm1Ska/Vdr^tm1Ska	NOD.Cg-Vdr^tm1Ska/CmatJ	MGI:3790970

Genotype
MGI:3664027

hm1

• Allelic Composition: Vdr^tm1Ska/Vdr^tm1Ska
• Genetic Background: involves: 129 * C57BL/6NCrlj * CBA/JNCrlj

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

behavior/neurological

abnormal response to new environment ( J:95324 )

• activity in the open field test did not decrease over time unlike in wild-type mice

abnormal startle reflex ( J:95324 )

• decreased within session habituation

impaired coordination ( J:95324 )

• fall off an accelerating or fixed speed rotating rod sooner than wild-type mice

abnormal locomotor activation ( J:95324 )

• bury fewer marbles and scatter less bedding

short stride length ( J:95324 )

• relatively normal gait but take shorter steps

decreased vertical activity ( J:95324 )

• in the holeboard and open field tests

decreased locomotor activity ( J:95324 )

• less active in a Y maze (traveling less total distance and making fewer arm entries), in a holeboard test (decreased distance traveled), in an elevated plus maze (lower distance traveled and number of closed arm entries), and in an open field test

growth/size/body

decreased body size ( J:95324 )

• shorter and lighter on a standard diet with 2 mM calcium in the water

nervous system

decreased prepulse inhibition ( J:95324 )

• at 256 ms but not 64 ms prepulse to pulse intervals

integument

alopecia ( J:95324 )

• variable severity in mice fed a standard diet with 2 mM calcium in the water

Genotype
MGI:2174799

hm2

• Allelic Composition: Vdr^tm1Ska/Vdr^tm1Ska
• Genetic Background: involves: C57BL/6NCrlj * CBA/JNCrlj

mortality/aging

premature death ( J:42054 , J:69822 )

• most mice died within 15 weeks of birth (J:42054)

• die at 6 - 7 weeks of age when fed a 0.02% calcium diet (J:69822)

craniofacial

flat face ( J:42054 )

short snout ( J:42054 )

growth/size/body

flat face ( J:42054 )

short snout ( J:42054 )

decreased body weight ( J:42054 , J:72578 )

• weigh about 50% of wild-type at 6 weeks of age (J:42054)

• mice weigh about 30% less than controls around 86 days of age (J:72578)

dermal cyst ( J:110729 )

• observed with thin hair sheaths at 3 weeks of age and contain tissue debris

• cyst size increases with age

postnatal growth retardation ( J:42054 , J:110729 )

• beginning after weaning (J:42054)

skeleton

abnormal limb bone morphology ( J:42054 )

abnormal fibula morphology ( J:42054 )

• appearance is similar to that of advanced rickets with widening of the epiphysis, thinning of the cortex, and fraying, cupping, and widening of the metaphysis

abnormal tibia morphology ( J:42054 )

• appearance is similar to that of advanced rickets with widening of the epiphysis, thinning of the cortex, and fraying, cupping, and widening of the metaphysis

abnormal long bone hypertrophic chondrocyte zone ( J:42054 )

• loss of columnar structure

increased long bone epiphyseal plate size ( J:42054 )

• widened in the tibia and fibula at 13 weeks of age

• layers of cartilage are wider with inadequate mineralization

abnormal long bone metaphysis morphology ( J:42054 )

• fraying, cupping, and widening of the metaphysis are seen in the tibia and fibula at 13 weeks of age

abnormal bone structure ( J:42054 )

decreased bone mineral density ( J:42054 , J:72578 )

• about a 40% reduction is detected at 7 weeks of age, but bone density is similar to wild-type prior to weaning (J:42054)

• mean femoral calcium levels are reduced by about 30% (J:72578)

decreased compact bone thickness ( J:42054 )

• thinning in the tibia and fibula at 13 weeks of age

increased osteoblast cell number ( J:42054 )

• bone surfaces in cancellous bone are surrounded by numerous osteoblastic cells

• osteoclast numbers are similar to wild-type

abnormal trabecular bone morphology ( J:42054 )

• in bone adjacent to the growth plates the extent and width of osteoid seems is increased and bone surfaces are surrounded by numerous osteoblastic cells

abnormal bone ossification ( J:42054 )

• impaired bone formation after weaning

abnormal bone mineralization ( J:112519 )

• low bone calcium when fed a normal diet

• bone calcium levels are similar to wild-type when mice are fed a high-lactose and are partially restored in mice on a high-fat diet

rickets ( J:72578 , J:110729 )

• is observed in these mice when fed a normal chow diet (J:72578)

• develop after 3 weeks of age (J:110729)

reproductive system

asthenozoospermia ( J:83237 )

♂ • increased motility observed after supplementatiom with estradiol and, to a lesser extent, calcium

abnormal female reproductive system morphology ( J:42054 )

♀

absent mature ovarian follicles ( J:42054 )

♀ • only primary and secondary follicles are seen at 7 weeks of age

uterus hypoplasia ( J:42054 )

♀ • at 7 weeks of age the uterus appears immature and hypoplastic; however uterine development is normal until 4 - 5 weeks of age

♀ • treatment with estrogen increases uterine size

abnormal gametogenesis ( J:83237 )

abnormal spermatogenesis ( J:83237 )

♂

oligozoospermia ( J:83237 )

♂ • sperm counts were approximately half of those of wild-type and heterozygous mice at 10 weeks of age

♂ • normal sperm counts in mice supplemented with estradiol

abnormal male reproductive system morphology ( J:83237 )

♂

dilated seminiferous tubule ( J:83237 )

♂ • dilation of tubules at 10 weeks of age with further dilation and atrophy at 15 weeks of age

♂ • seminiferous tubules of mice supplemented with estradiol are histologically indistinct from wild-type

increased testis weight ( J:83237 )

♂ • testicular weight was increased at 10 weeks of age relative to wild-type, however it was normal at 15 weeks of age

abnormal estrous cycle ( J:83237 )

♀ • females did not show labial swelling or reddening of vaginal membranes

abnormal fertility/fecundity ( J:42054 )

female infertility ( J:42054 , J:69822 )

♀ (J:42054)

♀ • when maintained on a nonpurified diet from weaning only 14% are fertile (J:69822)

♀ • however, when fed a 10% lactose diet or on a high calcium diet all mice are fertile and litter size is similar to wild-type (J:69822)

reduced female fertility ( J:69822 )

♀ • fertility is reduced when mice are on a 0.47% calcium diet

male infertility ( J:42054 , J:69822 )

♂ (J:42054)

♂ • when maintained on a nonpurified diet from weaning only 14% are fertile (J:69822)

♂ • however, when fed a 10% lactose diet or on a high calcium diet all mice are fertile (J:69822)

reduced male fertility ( J:69822 )

♂ • fertility is reduced when mice are on a 0.47% calcium diet

homeostasis/metabolism

abnormal blood homeostasis ( J:112519 )

• high serum osteocalcin levels when fed a normal diet

increased circulating follicle stimulating hormone level ( J:83237 )

• normal levels at 3 weeks of age

• levels were twice those of wild-type between 8 and 12 weeks of age

increased circulating luteinizing hormone level ( J:83237 )

• normal levels at 3 weeks of age

• 5- to 10-fold increase relative to wild-type at 8 weeks of age through 12 weeks of age

decreased circulating calcium level ( J:42054 , J:69822 , J:71459 , J:72578 , J:83237 , J:112519 )

• develops by 4 weeks of age (1 week after weaning) (J:42054)

• when fed a nonpurified, 0.47% calcium, or 0.02% calcium diet (J:69822)

• serum calcium levels are slightly but not significantly lower when mice are on high calcium, medium calcium, or 10% lactose diet (J:69822)

• mean serum calcium levels on a normal chow diet are 6.0 mg/dl compared to 8.6 in wild-type controls (J:72578)

decreased circulating phosphate level ( J:42054 )

• develops by 4 weeks of age

increased circulating alkaline phosphatase level ( J:42054 )

• serum activity is significantly elevated by 4 weeks of age

abnormal fat-soluble vitamin level ( J:71459 , J:112519 )

• serum levels of 1alpha,25-dihydroxyvitamin D₃ are increased about 50 fold and serum levels of 25-dihydroxyvitamin D₃ are decreased (J:71459)

abnormal vitamin D level ( J:42054 )

• serum levels of 1alpha,25-dihydroxyvitamin D₃ are increased about 10-fold and serum levels of 24,25-dihydroxyvitamin D₃ are decreased to almost undetectable levels at 4 and 7 weeks of age

• however, these levels are similar to wild-type prior to weaning

immune system

abnormal macrophage chemotaxis ( J:112519 )

• impaired chemotaxis capacity in response to casain or fnlpntl in mice on a normal diet but not in mice fed a high-lactose or high-fat diet

decreased splenocyte proliferation ( J:112519 )

• anti-CD3 stimulated proliferation is impaired in splenocytes from mice fed a normal diet but not in mice fed a high-fat diet

decreased susceptibility to autoimmune diabetes ( J:112519 )

• highly resistant to streptozotocin induced diabetes when fed a normal diet but not when fed a high-lactose or high-fat diet

dermatitis ( J:111828 )

• after 17 days of MC903 application to the ears

digestive/alimentary system

abnormal large intestine crypts of Lieberkuhn morphology ( J:71459 )

• in the sigmoid colon, the proliferative compartment is enlarged towards the upper part of the crypt and density of PCNA staining is increased

abnormal colon morphology ( J:71459 )

• in the descending colon more cells are positive for DNA oxidation and increased cell proliferation is seen

decreased intestinal calcium absorption ( J:72578 )

• mice have about a 3-fold lower ability to absorb calcium through the gut after being maintained on a low calcium diet

endocrine/exocrine glands

abnormal large intestine crypts of Lieberkuhn morphology ( J:71459 )

• in the sigmoid colon, the proliferative compartment is enlarged towards the upper part of the crypt and density of PCNA staining is increased

absent mature ovarian follicles ( J:42054 )

♀ • only primary and secondary follicles are seen at 7 weeks of age

dilated seminiferous tubule ( J:83237 )

♂ • dilation of tubules at 10 weeks of age with further dilation and atrophy at 15 weeks of age

♂ • seminiferous tubules of mice supplemented with estradiol are histologically indistinct from wild-type

increased testis weight ( J:83237 )

♂ • testicular weight was increased at 10 weeks of age relative to wild-type, however it was normal at 15 weeks of age

limbs/digits/tail

abnormal limb bone morphology ( J:42054 )

abnormal fibula morphology ( J:42054 )

• appearance is similar to that of advanced rickets with widening of the epiphysis, thinning of the cortex, and fraying, cupping, and widening of the metaphysis

abnormal tibia morphology ( J:42054 )

• appearance is similar to that of advanced rickets with widening of the epiphysis, thinning of the cortex, and fraying, cupping, and widening of the metaphysis

hematopoietic system

abnormal macrophage chemotaxis ( J:112519 )

• impaired chemotaxis capacity in response to casain or fnlpntl in mice on a normal diet but not in mice fed a high-lactose or high-fat diet

decreased splenocyte proliferation ( J:112519 )

• anti-CD3 stimulated proliferation is impaired in splenocytes from mice fed a normal diet but not in mice fed a high-fat diet

integument

integument phenotype ( J:111828 )

N • topical application of MC903 does not create an atopic dermatitis-like (AD) phenotype in null mice as in Vdr^tm1Pcn homozygotes

dermal cyst ( J:110729 )

• observed with thin hair sheaths at 3 weeks of age and contain tissue debris

• cyst size increases with age

dermatitis ( J:111828 )

• after 17 days of MC903 application to the ears

abnormal coat/ hair morphology ( J:110729 )

alopecia ( J:42054 , J:67149 , J:110729 )

• develops by 7 weeks of age (J:42054)

• mice develop a progressive form of alopecia that occurs with little skin inflammation (J:67149)

• seen in some mice by 6 weeks of age and in most by 3 months of age with near total hair loss by 8 months of age (J:110729)

dilated hair follicle ( J:110729 )

• at 3 weeks, hair follicles lacking hair shafts are dilated

sparse vibrissae ( J:42054 )

• few whiskers present at 7 weeks of age

decreased hair follicle cell proliferation ( J:110729 )

• decreased hair follicle proliferation

abnormal epidermis stratum granulosum morphology ( J:110729 )

• increase in the number of small dense granules with few or no surrounding keratin bundles and apparent absence of mature keratohyalin granules

abnormal skin development ( J:110729 )

• at 1 week of age, expression of differentiation markers in the epidermis is decreased compared to wild-type, but this difference is reduced by 3 weeks of age

cellular

oligozoospermia ( J:83237 )

♂ • sperm counts were approximately half of those of wild-type and heterozygous mice at 10 weeks of age

♂ • normal sperm counts in mice supplemented with estradiol

abnormal macrophage chemotaxis ( J:112519 )

• impaired chemotaxis capacity in response to casain or fnlpntl in mice on a normal diet but not in mice fed a high-lactose or high-fat diet

asthenozoospermia ( J:83237 )

♂ • increased motility observed after supplementatiom with estradiol and, to a lesser extent, calcium

decreased splenocyte proliferation ( J:112519 )

• anti-CD3 stimulated proliferation is impaired in splenocytes from mice fed a normal diet but not in mice fed a high-fat diet

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
osteoporosis		DOID:11476	OMIM:166710	J:83237
rickets		DOID:10609		J:42054 , J:83237

Genotype
MGI:3790970

hm3

• Allelic Composition: Vdr^tm1Ska/Vdr^tm1Ska
• Genetic Background: NOD.Cg-Vdr^tm1Ska/CmatJ

growth/size/body

postnatal growth retardation ( J:127787 )

• mice exhibit growth retardation

homeostasis/metabolism

decreased circulating calcium level ( J:127787 )

• hypocalcemia is found with high levels of the active metabolite of vitamin D in the sera of mice

abnormal glucose tolerance ( J:127787 )

• glucose tolerance is impaired compared to non-NOD mice but the results are identical when compared to NOD mice with wild-type VDR alleles

immune system

abnormal dendritic cell differentiation ( J:127787 )

• thymic and lymph node dendritic cells show defective maturation as indicated by low CD86 expression

abnormal T cell number ( J:127787 )

• there is a significant decrease in the number of double negative (CD4-CD8-) alphabeta T cells found in the spleen compared to littermate controls

decreased regulatory T cell number ( J:127787 )

• there are decreased numbers of CD4⁺CD25⁺ T cells found in the spleen, mesenteric lymph nodes and in the thymus

abnormal chemokine secretion ( J:127787 )

• activated macrophages make significantly less CCL2 when activated in vitro with LPS

abnormal interleukin-1 secretion ( J:127787 )

• there is almost a 4-fold reduction in the amount of IL-1 produced by macrophages when activated by LPS in vitro

• resting macrophages also produce significantly less IL-1

decreased interleukin-6 secretion ( J:127787 )

• there is a 2-fold reduction in the amount of IL-6 produced by macrophages when activated by LPS in vitro

• resting macrophages also produce less IL-6

increased susceptibility to autoimmune diabetes ( J:127787 )

• mice develop insulitis and diabetes at the same rate as NOD mice with wild-type VDR alleles

• the incidence of diabetes by 250 days of age was 50% in males and 67% in females at N10, and 30% in males and 69% in females at N10

• mean onset of disease for male mice is 163 days and for female mice 142 days

hematopoietic system

abnormal dendritic cell differentiation ( J:127787 )

• thymic and lymph node dendritic cells show defective maturation as indicated by low CD86 expression

abnormal T cell number ( J:127787 )

• there is a significant decrease in the number of double negative (CD4-CD8-) alphabeta T cells found in the spleen compared to littermate controls

decreased regulatory T cell number ( J:127787 )

• there are decreased numbers of CD4⁺CD25⁺ T cells found in the spleen, mesenteric lymph nodes and in the thymus

skeleton

increased long bone epiphyseal plate size ( J:127787 )

• mice have widened growth plates that are hypomineralized

decreased bone mineral density ( J:127787 )

• decreased bone mineral density is observed along with less trabeculae and thicker osteoid seams

integument

alopecia ( J:127787 )

• mice exhibit alopecia

cellular

abnormal dendritic cell differentiation ( J:127787 )

• thymic and lymph node dendritic cells show defective maturation as indicated by low CD86 expression