Phenotypes associated with this allele

• Allele Symbol: Vdr^tm1Mbd
• Allele Name: targeted mutation 1, Marie B Demay
• Allele ID: MGI:2183404
• Summary: 8 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Vdr^tm1Mbd/Vdr^tm1Mbd	involves: 129S4/SvJae	MGI:3588584
hm2	Vdr^tm1Mbd/Vdr^tm1Mbd	involves: 129S4/SvJae * C57BL/6	MGI:3798087
hm3	Vdr^tm1Mbd/Vdr^tm1Mbd	involves: 129S4/SvJae * C57BL/6J	MGI:3779048
ht4	Vdr^tm1Mbd/Vdr^+	involves: 129S4/SvJae	MGI:5501523
ht5	Vdr^tm1Mbd/Vdr^+	involves: 129S4/SvJae * C57BL/6	MGI:3798173
cx6	Il10^tm1Cgn/Il10^tm1Cgn Vdr^tm1Mbd/Vdr^tm1Mbd	involves: 129P2/OlaHsd * 129S4/SvJae * C57BL/6	MGI:3798090
cx7	Cyp24a1^tm1Star/Cyp24a1^tm1Star Vdr^tm1Mbd/Vdr^tm1Mbd	involves: 129S4/SvJae	MGI:3694743
cx8	Tg(VDR*L233S,luc)T807Pike/0 Vdr^tm1Mbd/Vdr^tm1Mbd	involves: 129S4/SvJae * C57BL/6	MGI:5662066

Genotype
MGI:3588584

hm1

• Allelic Composition: Vdr^tm1Mbd/Vdr^tm1Mbd
• Genetic Background: involves: 129S4/SvJae

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

Alopecia in 3.5 month old Vdr^tm1Mbd/Vdr^tm1Mbd (right) mice

endocrine/exocrine glands

enlarged parathyroid gland ( J:42815 )

• more than 10-fold increase in parathyroid gland size of 70-day-old mice

growth/size/body

increased heart weight ( J:78067 )

• heart weight to body weight ratio is significantly higher than control

decreased body weight ( J:42815 )

• weigh 10% less than controls by 91 days of age; weight is normal at birth

dermal cyst ( J:42815 )

postnatal growth retardation ( J:42815 )

• from 24 days of age, fail to grow as rapidly as controls

homeostasis/metabolism

increased circulating angiotensin II level ( J:78067 )

• circulating levels of angiotensin II are higher

increased circulating parathyroid hormone level ( J:42815 , J:63291 , J:78067 )

• starting on day 21, exhibit a progressive increase in parathyroid hormone levels (J:42815)

• serum PTH concentration is increased 150-fold by 3 months of age (J:78067)

• treatment with HCa-Lac (calcium, phosphorus, lactose) diet for 5 weeks lowers PTH concentration to 7-fold higher than control (J:78067)

decreased circulating calcium level ( J:42815 , J:78067 )

• become progressively hypocalcemic after day 21, maintaining ionized calcium levels about 25% lower than controls (J:42815)

• blood ionized calcium levels are decreased by 30% (J:78067)

• treatment with HCa-Lac (calcium, phosphorus, lactose) diet for 5 weeks normalizes calcium levels (J:78067)

increased circulating angiotensinogen level ( J:78067 )

• plasma angiotensinogen II levels are increased more than 2.5 fold compared to wildtype, however, expression of angiotensinogen is the same as wildtype

• on a high salt (8%) diet, plasma angiotensinogen II levels are significantly increased over treated control

• plasma angiotensinogen II levels are increased following 24 hour dehydration, however, levels for treated control exhibit a comparatively higher increase

increased circulating renin level ( J:78067 )

• renin is increased in the afferent glomerular arterioles as determined by immunoreactivity

increased urine potassium level ( J:78067 )

• mice excrete 19% more potassium in urine, however, blood potassium concentration is normal

increased urine sodium level ( J:78067 )

• mice excrete 37% more sodium in urine, however, blood sodium concentration is normal

increased renin activity ( J:78067 )

• circulating levels of angiotensin II are higher but liver levels of the angiotensinogen precursor are normal suggesting increased renin activity

skeleton

short femur ( J:42815 )

• femurs are about 15% shorter

abnormal tibia morphology ( J:42815 )

• decreased cortical width along the diaphysis and expansion and flaring of the growth plate at 35 days of age

short tibia ( J:42815 )

• tibias are about 15% shorter

increased width of hypertrophic chondrocyte zone ( J:42815 )

• 15% increase in the number of hypertrophic chondrocytes per column in the tibia and vertebra of 15 day old mice and increased hypertrophic chondrocyte zone in 35 day old growth plate

disorganized long bone epiphyseal plate ( J:42815 )

• 35 day old growth plate is disorganized with an increase in vascularity and matrix

abnormal bone mineralization ( J:42815 )

• decreased bone mineralization in 35 day old mice but not 15 day old mice

rickets ( J:42815 )

limbs/digits/tail

short femur ( J:42815 )

• femurs are about 15% shorter

abnormal tibia morphology ( J:42815 )

• decreased cortical width along the diaphysis and expansion and flaring of the growth plate at 35 days of age

short tibia ( J:42815 )

• tibias are about 15% shorter

behavior/neurological

increased fluid intake ( J:78067 )

• mice drink approximately twice as much water as controls, however, glucose and insulin levels are normal

cardiovascular system

increased heart weight ( J:78067 )

• heart weight to body weight ratio is significantly higher than control

hypertension ( J:78067 )

• mice are hypertensive with high systolic and the diastolic blood pressures caused in part by high circulating levels of renin and angiotensin II

increased systemic arterial diastolic blood pressure ( J:78067 )

• diastolic blood pressure is significantly higher (>20 mmHg) than those of wild-type littermates

increased systemic arterial systolic blood pressure ( J:78067 )

• systolic blood pressure is significantly higher (>20 mmHg) than those of wild-type littermates

renal/urinary system

increased urine potassium level ( J:78067 )

• mice excrete 19% more potassium in urine, however, blood potassium concentration is normal

increased urine sodium level ( J:78067 )

• mice excrete 37% more sodium in urine, however, blood sodium concentration is normal

polyuria ( J:78067 )

integument

dermal cyst ( J:42815 )

alopecia ( J:42815 )

• at 4 weeks of age, begin to develop perioral and periorbital alopecia

• hair loss progresses to the entire body over the next 3 months, with more rapid progression in females than males

dilated hair follicle ( J:42815 )

• dilation of the hair follicles

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
rickets		DOID:10609		J:42815

Genotype
MGI:3798087

hm2

• Allelic Composition: Vdr^tm1Mbd/Vdr^tm1Mbd
• Genetic Background: involves: 129S4/SvJae * C57BL/6

mortality/aging

increased susceptibility to xenobiotic induced morbidity/mortality ( J:130511 )

• up to 70% of mutants treated with DSS to induce colitis die within 2 weeks, compared to no mortality in treated wild-type

growth/size/body

increased heart weight ( J:120340 , J:120353 )

• heart weight to body weight ratio is increased to 6.9 from 4.9 in wild-type at 12 months (J:120340)

• heart weight to body weight ratio is increased 41% relative to wild-type (J:120353)

cardiac hypertrophy ( J:120340 )

• heart tissue displays increased cell size

weight loss ( J:130511 )

• mice treated with 2.5% DSS lose up to 15% of body weight within 8 days after treatment, compared to almost no weight loss in treated wild-type

digestive/alimentary system

abnormal intestinal epithelium morphology ( J:130511 )

• severely distrupted and opened tight junctions and desmosomes are seen in colonic epithelia of DSS-treated mutants; in treated wild-type, epithelia appear normal

abnormal intestinal mucosa morphology ( J:130511 )

• erosions of mucosa of colon are observed on day 3 with 2.5% DSS treatment and substantial ulcerations are seen by day 7, while wild-type mice show no or some focal damage to mucosa on day 3 and day 7

• in mice treated with 2% DSS for 2 or 3 days, transepithelial electrical resistance (TER) is significantly reduced even in absence of clinical symptoms of colitis, compared to controls, indicating impaired mucosal barrier integrity

abnormal large intestine crypts of Lieberkuhn morphology ( J:130511 )

• in some colon segments, ulceration is so severe that entire crypt structure is lost

• no new crypts form around ulcers in mutants

intestinal ulcer ( J:130511 )

• severe ulceration is seen on day 7 of treatment for 7 days

• by day 10, some epithelial cells appear to cover ulcerations, but very little cell proliferation or healing is seen compared to wild-type mice which show healing and reepithelization of ulcers with new crypts forming around ulcers at equivalent time point

intestinal inflammation ( J:107077 )

• spontaneous inflammatory bowel disease (IBD) develops

increased susceptibility to induced colitis ( J:130511 )

• mice treated with 2.5% dextran sodium sulfate (DSS) for 1 week show more severe colitis development than treated wild-type

immune system

immune system phenotype ( J:107077 )

N • at 5 weeks, thymi are not different than in wild-type

intestinal inflammation ( J:107077 )

• spontaneous inflammatory bowel disease (IBD) develops

increased susceptibility to induced colitis ( J:130511 )

• mice treated with 2.5% dextran sodium sulfate (DSS) for 1 week show more severe colitis development than treated wild-type

increased thymus weight ( J:107077 )

• increases with time and IBD

thymus hyperplasia ( J:107077 )

• increases with time and IBD

abnormal interleukin level ( J:107077 )

• Il-1beta is expressed in the colon; older mutants (>9 months) display 10-fold higher levels than younger mice, whereas wild-type controls do not express any cytokines in the colon at any age

abnormal tumor necrosis factor level ( J:107077 )

• low levels of expression are detected in colons of young animals, and levels are 20-fold higher in older mice (>9 months)

hematopoietic system

increased thymus weight ( J:107077 )

• increases with time and IBD

thymus hyperplasia ( J:107077 )

• increases with time and IBD

cardiovascular system

cardiovascular system phenotype ( J:120353 )

N • plasma levels of angiotensin II or aldosterone are not different from wild-type

N • ECG analysis does not reveal any significant differences from wild-type at 3, 6, or 9 months

increased heart weight ( J:120340 , J:120353 )

• heart weight to body weight ratio is increased to 6.9 from 4.9 in wild-type at 12 months (J:120340)

• heart weight to body weight ratio is increased 41% relative to wild-type (J:120353)

cardiac hypertrophy ( J:120340 )

• heart tissue displays increased cell size

cardiac fibrosis ( J:120340 )

• heart tissue displays increased collagen deposition primarily in the extracellular matrix

abnormal myocardial fiber physiology ( J:131143 )

decreased systemic arterial systolic blood pressure ( J:120353 )

• at 9 months, pressure is significantly lower than in wild-type

endocrine/exocrine glands

abnormal large intestine crypts of Lieberkuhn morphology ( J:130511 )

• in some colon segments, ulceration is so severe that entire crypt structure is lost

• no new crypts form around ulcers in mutants

increased thymus weight ( J:107077 )

• increases with time and IBD

thymus hyperplasia ( J:107077 )

• increases with time and IBD

homeostasis/metabolism

abnormal interleukin level ( J:107077 )

• Il-1beta is expressed in the colon; older mutants (>9 months) display 10-fold higher levels than younger mice, whereas wild-type controls do not express any cytokines in the colon at any age

abnormal tumor necrosis factor level ( J:107077 )

• low levels of expression are detected in colons of young animals, and levels are 20-fold higher in older mice (>9 months)

abnormal enzyme/coenzyme activity ( J:120340 )

• matrix metalloproteinase-2 and -9 activities in heart tissue (ventricular) are increased relative to wild-type

abnormal renin activity ( J:120353 )

• plasma renin activity is increased by 50% but difference from wild-type activity is not significant

increased susceptibility to xenobiotic induced morbidity/mortality ( J:130511 )

• up to 70% of mutants treated with DSS to induce colitis die within 2 weeks, compared to no mortality in treated wild-type

Genotype
MGI:3779048

hm3

• Allelic Composition: Vdr^tm1Mbd/Vdr^tm1Mbd
• Genetic Background: involves: 129S4/SvJae * C57BL/6J

Expansion of the growth plate and decrease in hypertrophic chondrocyte apoptosis in Phex^Hyp/? and Vdr^tm1Mbd/Vdr^tm1Mbd mice

homeostasis/metabolism

abnormal mineral homeostasis ( J:99866 )

decreased circulating phosphate level ( J:99866 )

skeleton

increased width of hypertrophic chondrocyte zone ( J:99866 )

• expansion of the growth plate is associated with impaired apoptosis of late hypertrophic chondrocytes

abnormal chondrocyte morphology ( J:99866 )

• impaired hypertrophic chondrocyte apoptosis

• a 'rescue diet' of high-calcium/low-phosphate restores the normal level of apoptosis and the growth plate phenotype

rickets ( J:99866 )

• mutants develop rickets secondary to impaired apoptosis of late hypertrophic chondrocytes

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
rickets		DOID:10609		J:99866

Genotype
MGI:5501523

ht4

• Allelic Composition: Vdr^tm1Mbd/Vdr⁺
• Genetic Background: involves: 129S4/SvJae

skeleton

increased bone mineral density ( J:196471 )

• at 16 weeks

increased trabecular bone volume ( J:196471 )

increased bone mass ( J:196471 )

• without overt rachitic abnormalities

Genotype
MGI:3798173

ht5

• Allelic Composition: Vdr^tm1Mbd/Vdr⁺
• Genetic Background: involves: 129S4/SvJae * C57BL/6

cardiovascular system

cardiovascular system phenotype ( J:120353 )

N • plasma levels of angiotensin II or aldosterone are not different from wild-type

N • ECG analysis does not reveal any significant differences from wild-type at 3, 6, or 9 months

increased heart weight ( J:120353 )

• heart weight to body weight ratio is increased 14% relative to wild-type

growth/size/body

increased heart weight ( J:120353 )

• heart weight to body weight ratio is increased 14% relative to wild-type

Genotype
MGI:3798090

cx6

• Allelic Composition: Il10^tm1Cgn/Il10^tm1Cgn; Vdr^tm1Mbd/Vdr^tm1Mbd
• Genetic Background: involves: 129P2/OlaHsd * 129S4/SvJae * C57BL/6

digestive/alimentary system

rectal prolapse ( J:107077 )

• 80% of double null animals develop rectal prolapse; seen at 5 weeks of age and beyond

intestinal inflammation ( J:107077 )

• mice develop spontaneous inflammatory bowel disease (IBD) involving the entire intestinal tract

colitis ( J:107077 )

• colon exhibits the most dramatic changes in gross anatomy and inflammation

immune system

increased T cell apoptosis ( J:107077 )

• thymocytes are more susceptible to apoptosis than in single null mice (10% of total cells are apoptotic vs 1%)

decreased T cell proliferation ( J:107077 )

• CD4+ and CD8+ T cells show reduced proliferative capacity compared to those of single null or wild-type mice when stimulated with anti-CD3 antibodies

intestinal inflammation ( J:107077 )

• mice develop spontaneous inflammatory bowel disease (IBD) involving the entire intestinal tract

colitis ( J:107077 )

• colon exhibits the most dramatic changes in gross anatomy and inflammation

abnormal thymus corticomedullary boundary morphology ( J:107077 )

• animals with progressive disease have thymuses with no clear corticomedullary demarcation, scattered cortical cells and accumulation of thymocytes in medulla

thymus hypoplasia ( J:107077 )

• thymus cellularity declines rapidly as mice develop IBD

abnormal thymus involution ( J:107077 )

• accelerated in animals with severe IBD

enlarged spleen ( J:107077 )

• spleens are 2-fold larger than in single null or wild-type mice

increased neutrophil cell number ( J:107077 )

• circulating neutrophil numbers are 4-fold higher than in single null or wild-type mice with IBD

decreased lymphocyte cell number ( J:107077 )

• lymphocyte cell counts are 2-fold lower than in single null or wild-type mice with IBD

increased macrophage cell number ( J:107077 )

• F4/80/CD11 macrophages are more numerous than in spleens of single null or wild-type mice with IBD

increased spleen red pulp amount ( J:107077 )

• red pulp is expanded and congested with accumulation of red blood cells with IBD

absent spleen white pulp ( J:107077 )

• there is almost complete absence of white pulp in spleens of double null mice with IBD

abnormal splenic cell ratio ( J:107077 )

• overall cellularity is reduced, with about 50% of CD4+, CD8+, and B cell numbers in single null or wild-type mice

abnormal CD4-positive, alpha-beta T cell physiology ( J:107077 )

• CD4+ T cells have a memory phenotype with high expression of CD44 and low expression of CD62L, while T cells from single null and wild-type mice have a nae phenotype

abnormal cytokine level ( J:107077 )

• 2-3-fold higher mRNA levels of Il-1beta, Il-2, TNFalpha and IFNgamma than found in single null mice are detected in colons; Il-12p35 and p40 are detected in double null colons, but not in single mutants

enlarged mesenteric lymph nodes ( J:107077 )

• MLN are 3- to 4-fold higher; cell numbers are increased relative to other lines of mice

abnormal lymph node cell ratio ( J:107077 )

• absolute numbers of CD4+ and CD8+ T cells are 3-fold higher in mesenteric lymph nodes (MLN)

hematopoietic system

increased T cell apoptosis ( J:107077 )

• thymocytes are more susceptible to apoptosis than in single null mice (10% of total cells are apoptotic vs 1%)

decreased T cell proliferation ( J:107077 )

• CD4+ and CD8+ T cells show reduced proliferative capacity compared to those of single null or wild-type mice when stimulated with anti-CD3 antibodies

abnormal thymus corticomedullary boundary morphology ( J:107077 )

• animals with progressive disease have thymuses with no clear corticomedullary demarcation, scattered cortical cells and accumulation of thymocytes in medulla

thymus hypoplasia ( J:107077 )

• thymus cellularity declines rapidly as mice develop IBD

abnormal thymus involution ( J:107077 )

• accelerated in animals with severe IBD

enlarged spleen ( J:107077 )

• spleens are 2-fold larger than in single null or wild-type mice

anemia ( J:107077 )

• mice have decreased erythrocyte numbers and lower hemoglobin concentrations than single null or wild-type mice with IBD

increased neutrophil cell number ( J:107077 )

• circulating neutrophil numbers are 4-fold higher than in single null or wild-type mice with IBD

decreased lymphocyte cell number ( J:107077 )

• lymphocyte cell counts are 2-fold lower than in single null or wild-type mice with IBD

increased macrophage cell number ( J:107077 )

• F4/80/CD11 macrophages are more numerous than in spleens of single null or wild-type mice with IBD

increased spleen red pulp amount ( J:107077 )

• red pulp is expanded and congested with accumulation of red blood cells with IBD

absent spleen white pulp ( J:107077 )

• there is almost complete absence of white pulp in spleens of double null mice with IBD

abnormal splenic cell ratio ( J:107077 )

• overall cellularity is reduced, with about 50% of CD4+, CD8+, and B cell numbers in single null or wild-type mice

abnormal CD4-positive, alpha-beta T cell physiology ( J:107077 )

• CD4+ T cells have a memory phenotype with high expression of CD44 and low expression of CD62L, while T cells from single null and wild-type mice have a nae phenotype

homeostasis/metabolism

abnormal cytokine level ( J:107077 )

• 2-3-fold higher mRNA levels of Il-1beta, Il-2, TNFalpha and IFNgamma than found in single null mice are detected in colons; Il-12p35 and p40 are detected in double null colons, but not in single mutants

cellular

increased T cell apoptosis ( J:107077 )

• thymocytes are more susceptible to apoptosis than in single null mice (10% of total cells are apoptotic vs 1%)

decreased T cell proliferation ( J:107077 )

• CD4+ and CD8+ T cells show reduced proliferative capacity compared to those of single null or wild-type mice when stimulated with anti-CD3 antibodies

endocrine/exocrine glands

abnormal thymus corticomedullary boundary morphology ( J:107077 )

• animals with progressive disease have thymuses with no clear corticomedullary demarcation, scattered cortical cells and accumulation of thymocytes in medulla

thymus hypoplasia ( J:107077 )

• thymus cellularity declines rapidly as mice develop IBD

abnormal thymus involution ( J:107077 )

• accelerated in animals with severe IBD

growth/size/body

enlarged spleen ( J:107077 )

• spleens are 2-fold larger than in single null or wild-type mice

Genotype
MGI:3694743

cx7

• Allelic Composition: Cyp24a1^tm1Star/Cyp24a1^tm1Star; Vdr^tm1Mbd/Vdr^tm1Mbd
• Genetic Background: involves: 129S4/SvJae

skeleton

skeleton phenotype ( J:63457 )

N • abnormalities in membranous bone formation seen in Cyp24a1^tm1Star are rescued in double homozygotes

Genotype
MGI:5662066

cx8

• Allelic Composition: Tg(VDR*L233S,luc)T807Pike/0; Vdr^tm1Mbd/Vdr^tm1Mbd
• Genetic Background: involves: 129S4/SvJae * C57BL/6

endocrine/exocrine glands

parathyroid gland hyperplasia ( J:218709 )

increased activity of parathyroid ( J:218709 )

• hyperparathyroidism

homeostasis/metabolism

increased circulating parathyroid hormone level ( J:218709 )

• parathyroid hormone levels are elevated even more than in single homozygous Vdr mutants

decreased circulating calcium level ( J:218709 )

decreased circulating phosphate level ( J:218709 )

skeleton

short tibia ( J:218709 )

• reduction in tibia length

decreased bone mineral density ( J:218709 )

• decrease in total body bone mineral density and in femur and spine bone mineral density

• bone loss is exaggerated at all sites compared to single homozygous Vdr mutants

decreased bone mineral density of femur ( J:218709 )

abnormal epiphyseal plate morphology ( J:218709 )

• disorganized growth plate

abnormal skeleton physiology ( J:218709 )

• aberrant skeletal growth

rickets ( J:218709 )

limbs/digits/tail

short tibia ( J:218709 )

• reduction in tibia length

integument

integument phenotype ( J:218709 )

N • mice show full rescue of the alopecia that is seen in single homozygous Vdr mutants and mice are able to initiate hair growth after depilation

N • mice exhibit normal epidermal morphology complete with the presence of hair follicles

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
rickets		DOID:10609		J:218709