Phenotypes associated with this allele

• Allele Symbol: Pthlh^tm1Hmk
• Allele Name: targeted mutation 1, Henry M Kronenberg
• Allele ID: MGI:2154515
• Summary: 18 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Pthlh^tm1Hmk/Pthlh^tm1Hmk	either: (involves: 129S2/SvPas) or (involves: 129S2/SvPas * C57BL/6)	MGI:3583956
hm2	Pthlh^tm1Hmk/Pthlh^tm1Hmk	involves: 129S2/SvPas	MGI:3717414
hm3	Pthlh^tm1Hmk/Pthlh^tm1Hmk	involves: 129S2/SvPas * C57BL/6	MGI:3510231
hm4	Pthlh^tm1Hmk/Pthlh^tm1Hmk	involves: 129S2/SvPas * C57BL/6J	MGI:2665250
ht5	Pthlh^tm1Hmk/Pthlh^+	involves: 129S2/SvPas	MGI:3617819
ht6	Pthlh^tm1Hmk/Pthlh^+	involves: 129S2/SvPas * C57BL/6	MGI:3510232
cn7	Pthlh^tm1Ack/Pthlh^tm1Hmk Tmem163^Tg(ACTB-cre)2Mrt/0	involves: 129 * BALB/c * FVB/N	MGI:3617820
cn8	Pthlh^tm1Ack/Pthlh^tm1Hmk Tg(LGB-cre)74Acl/0	involves: 129 * C57BL/6 * CBA	MGI:3617822
cn9	Pthlh^tm1Hmk/Pthlh^+ Pth1r^tm1Hmk/Pth1r^tm2Hmk Tg(Bglap2-cre)1Kry/0	involves: 129S2/SvPas * 129S4/SvJae * C57BL/6 * FVB/N	MGI:3584345
cn10	Pthlh^tm1Hmk/Pthlh^tm1Hmk Pth1r^tm1Hmk/Pth1r^tm2Hmk Tg(Bglap2-cre)1Kry/0 Tg(Col2a1-PTHLH)1Ecw/0	involves: 129S2/SvPas * 129S4/SvJae * C57BL/6 * FVB * SJL	MGI:3584347
cx11	Pthlh^tm1Hmk/Pthlh^tm1Hmk Pth1r^tm1Hmk/Pth1r^tm2Hmk Tg(Col2a1-PTHLH)1Ecw/0	involves: 129S2/SvPas * 129S4/SvJae * C57BL/6 * SJL	MGI:3584346
cx12	Pthlh^tm1Hmk/Pthlh^tm1Hmk Tg(Col2a1-PTHR1*H223R)AHju/Tg(Col2a1-PTHR1*H223R)AHju	involves: 129S2/SvPas * C57BL/6	MGI:3584031
cx13	Pthlh^tm1Hmk/Pthlh^+ Tg(Col2a1-GAL4)1Amc/0 Tg(UAS-IHH)1Amc/0	involves: 129S2/SvPas * C57BL/6	MGI:3584341
cx14	Pthlh^tm1Hmk/Pthlh^tm1Hmk Tg(Col2a1-GAL4)1Amc/0 Tg(Col2a1-PTHR1*H223R)AHju/? Tg(UAS-IHH)1Amc/0	involves: 129S2/SvPas * C57BL/6	MGI:3584352
cx15	Pthlh^tm1Hmk/Pthlh^tm1Hmk Tg(Col2a1-PTHR1*H223R)AHju/0	involves: 129S2/SvPas * C57BL/6	MGI:3717204
cx16	Pth^tm1Dgo/Pth^tm1Dgo Pthlh^tm1Hmk/Pthlh^tm1Hmk	involves: 129S2/SvPas * C57BL/6J	MGI:2665233
cx17	Pthlh^tm1Hmk/Pthlh^tm1Hmk Tg(Col2a1-PTHLH)2Ecw/0 Tg(KRT14-PTHLH)7Wmp/0	involves: 129S2/SvPas * C57BL/6 * SJL	MGI:3717420
cx18	Pthlh^tm1Hmk/Pthlh^tm1Hmk Tg(Col2a1-PTHLH)2Ecw/0	involves: 129S2/SvPas * C57BL/6 * SJL	MGI:3717417

Genotype
MGI:3583956

hm1

• Allelic Composition: Pthlh^tm1Hmk/Pthlh^tm1Hmk
• Genetic Background: either: (involves: 129S2/SvPas) or (involves: 129S2/SvPas * C57BL/6)

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

mortality/aging

perinatal lethality, complete penetrance ( J:16911 )

• mice die immediately after birth

respiratory system

respiratory failure ( J:16911 )

• mice make feeble attempts to breathe

homeostasis/metabolism

cyanosis ( J:16911 )

• skin remains bluish-grey until death

skeleton

abnormal long bone morphology ( J:16911 )

• long bones are shorter, thicker, and deformed with mildy splayed ends

abnormal long bone metaphysis morphology ( J:16911 )

• irregular metaphyseal margins in the long bones

decreased length of long bones ( J:16911 )

increased diameter of long bones ( J:16911 )

abnormal axial skeleton morphology ( J:16911 )

short mandible ( J:16911 )

domed cranium ( J:16911 )

short sternum ( J:16911 )

abnormal rib morphology ( J:16911 )

short ribs ( J:16911 )

splayed ribs ( J:16911 )

abnormal thoracic cage shape ( J:16911 )

• the thoracic cage is narrow and bell-shaped

abnormal vertebral body morphology ( J:16911 )

• smaller in height and exhibit advanced ossification involving both the vertebral bodies and the articular processes

abnormal bone trabecula morphology ( J:16911 )

• bony trabeculae of the primary spongiosa are shortened and distorted

abnormal skeleton development ( J:16911 )

abnormal long bone epiphyseal plate morphology ( J:16911 )

• zone of resting chondrocytes and the zones of proliferation and maturation are shortened, however the numbers of multinucleated chondroclasts and osteoclasts are normal

abnormal long bone epiphyseal plate proliferative zone ( J:16911 )

• columns of proliferating chondrocytes are shorter and irregularly arranged

abnormal cartilage development ( J:16911 )

• cartilage primorida of the ulna and radious are deformed and shortened at E14.5 but not at E12.5

chondrodystrophy ( J:16911 )

• exhibit osteochondrodysplasia

abnormal bone mineralization ( J:16911 )

• excessive/advanced mineralization

premature endochondral bone ossification ( J:16911 )

• exhibit acceleration of the normal endochondral ossification process and also abnormal maturation of hyaline rib chondrocytes with associated perichondral ossification

limbs/digits/tail

short limbs ( J:16911 )

craniofacial

short mandible ( J:16911 )

domed cranium ( J:16911 )

protruding tongue ( J:16911 )

short snout ( J:16911 )

digestive/alimentary system

protruding tongue ( J:16911 )

growth/size/body

protruding tongue ( J:16911 )

short snout ( J:16911 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
achondroplasia		DOID:4480	OMIM:100800	J:16911
Albright's hereditary osteodystrophy		DOID:0080053	OMIM:103580	J:16911

Genotype
MGI:3717414

hm2

• Allelic Composition: Pthlh^tm1Hmk/Pthlh^tm1Hmk
• Genetic Background: involves: 129S2/SvPas

Skeletal phenotypes of wild type, Tg(Col2a1-PTHLH)2Ecw/0, Pthlh^tm1Hmk/Pthlh^tm1Hmk, and Pthlh^tm1Hmk/Pthlh^tm1Hmk Tg(Col2a1-PTHLH)2Ecw/0 mice

skeleton

abnormal sternum ossification ( J:50144 )

• inappropriate ossification of the costal cartilage and along the length of the sternum

abnormal bone mineralization ( J:50144 )

• accelerated mineralization of the endochondral bones of the cranial base

Genotype
MGI:3510231

hm3

• Allelic Composition: Pthlh^tm1Hmk/Pthlh^tm1Hmk
• Genetic Background: involves: 129S2/SvPas * C57BL/6

Alizarin red S stained skeletal images of hemizygous and homozygous Tg(Col2a1-PTHR1*H223R)AHju and Pthlh^tm1Hmk/Pthlh^tm1Hmk mice

mortality/aging

perinatal lethality, complete penetrance ( J:90274 )

• mice die at birth due to respiratory failure

respiratory system

abnormal lung morphology ( J:90274 )

• at E18.5 and at term (E19.0?E19.5), mutant lungs are denser and less-well aerated than control lungs

abnormal lung development ( J:90274 )

• at E18.5, distal airways display immature features consistent with an arrest at the canalicular stage of lung development

• in vitro, E13.5 and E14.5 lung buds cultured in the absence of thoracic volume constriction or systemic compensating factors display delayed type II alveolar cell and mesenchymal differentiation; however, addition of exogenous PTHLH restores interstitial cell morphology

abnormal mesenchymal cell differentiation involved in lung development ( J:90274 )

• in vitro, E13.5 and E14.5 lung buds cultured in the absence of thoracic volume constriction or systemic compensating factors display delayed mesenchymal differentiation

abnormal lung saccule morphology ( J:90274 )

• at E18.5, distinct saccules are absent and the % of lung tissue occupied by potential air spaces is reduced by ~50%

• at E18.5, mature saccular septa are absent

small lung saccule ( J:90274 )

• at E18.5, the mean area per saccule is reduced by ~50%

thick lung-associated mesenchyme ( J:90274 )

• at E18.5, the septal mesenchyme displays an abnormal thickness and cellularity that is typical of canalicular-stage lung

abnormal pulmonary alveolus epithelium morphology ( J:90274 )

• at E18.5, the cuboidal epithelium shows a significantly greater nuclear:cell area ratio

absent type I pneumocytes ( J:90274 )

• at E18.5, thin type I-like epithelial cells are absent, unlike in wild-type lungs

abnormal type II pneumocyte morphology ( J:90274 )

• at E18.5, type II cells appear immature: only rounded to columnar cells with poorly differentiated cytoplasm, rare apical microvilli, large glycogen lakes, and few precursor multilamellar inclusion bodies or mature lamellar bodies are observed

decreased alveolar lamellar body number ( J:90274 )

• at E18.5, few precursor multilamellar inclusion bodies or mature lamellar bodies are observed

abnormal lung interstitium morphology ( J:90274 )

• at E18.5, the septal mesenchyme displays an abnormal thickness and cellularity that is typical of canalicular-stage lung

• at E18.5, lung interstitia display immature fibroblastic cells that lack a conspicuous endoplasmic reticulum and Golgi complex

• many interstitial fibroblasts are packed with numerous lipid droplets, unlike in wild-type lungs

• areas of unremodeled basal lamina are observed, unlike in wild-type lungs

small lung ( J:90274 )

• at E18.5 and at term, mutant lungs are smaller than control lungs

• however, lung weights are not significantly altered

atelectasis ( J:90274 )

• lungs removed from spontaneously delivered mice fail to float in saline solution

respiratory failure ( J:90274 )

• mice die at birth due to respiratory failure

decreased surfactant secretion ( J:90274 )

• at E17.5 and E18.5, [3H]choline incorporation into surfactant phospholipid is reduced to one third of that seen in control lungs, consistent with a higher glycogen content

• notably, mRNA levels for surfactant protein (SP)-A, SP-B, and SP-C are not significantly altered in mice at E19

• in vitro, E14.5 lungs maintained in serumless organ culture for 4 days show a >40% inhibition of surfactant phospholipid production; however, addition of exogenous PTHLH restores surfactant phospholipid production to normal levels

skeleton

short mandible ( J:77639 )

domed cranium ( J:77639 )

abnormal long bone morphology ( J:77639 )

• deformed long bones

decreased long bone epiphyseal plate size ( J:77639 )

• diminished height of growth plate cartilage

decreased length of long bones ( J:77639 )

premature bone ossification ( J:77639 )

• premature ossification of the synchondrosis between the basoccipital bone and the basisphenoid bone

craniofacial

short mandible ( J:77639 )

domed cranium ( J:77639 )

growth/size/body

small thoracic cavity ( J:90274 )

• at E18.5, thoracic volume is reduced by >50%

cellular

abnormal mesenchymal cell differentiation involved in lung development ( J:90274 )

• in vitro, E13.5 and E14.5 lung buds cultured in the absence of thoracic volume constriction or systemic compensating factors display delayed mesenchymal differentiation

Genotype
MGI:2665250

hm4

• Allelic Composition: Pthlh^tm1Hmk/Pthlh^tm1Hmk
• Genetic Background: involves: 129S2/SvPas * C57BL/6J

Skeletal phenotypes and tibial histology of Pth^tm1Dgo/Pth^tm1Dgo, Pthlh^tm1Hmk/Pthlh^tm1Hmk and Pth^tm1Dgo/Pth^tm1Dgo Pthlh^tm1Hmk/Pthlh^tm1Hmk mice

cellular

increased chondrocyte apoptosis ( J:76407 )

• number of apoptotic chondrocytes is increased five-fold

increased osteoblast apoptosis ( J:76407 )

• increase in osteoblast apoptosis in the endosteum

increased osteocyte apoptosis ( J:76407 )

• increase in osteocyte apoptosis in the endosteum

mortality/aging

perinatal lethality, complete penetrance ( J:76407 )

• mutants die at birth

growth/size/body

disproportionate dwarf ( J:76407 )

• short limbed dwarfism

endocrine/exocrine glands

enlarged parathyroid gland ( J:76407 )

• moderately enlarged

limbs/digits/tail

short tibia ( J:76407 )

short limbs ( J:76407 )

skeleton

increased chondrocyte apoptosis ( J:76407 )

• number of apoptotic chondrocytes is increased five-fold

increased osteoblast apoptosis ( J:76407 )

• increase in osteoblast apoptosis in the endosteum

increased osteocyte apoptosis ( J:76407 )

• increase in osteocyte apoptosis in the endosteum

decreased length of long bones ( J:76407 )

short tibia ( J:76407 )

abnormal bone structure ( J:76407 )

abnormal osteoclast morphology ( J:76407 )

• size of osteoclasts is decreased

decreased osteoclast cell number ( J:76407 )

increased compact bone thickness ( J:76407 )

increased osteoblast cell number ( J:76407 )

• increase in osteoblast numbers in the primary spongiosa and in the endosteum

abnormal trabecular bone morphology ( J:76407 )

• trabecular bone volume is somewhat increased

abnormal cartilage development ( J:76407 )

• reduction in cartilage mineralization

abnormal long bone epiphyseal plate proliferative zone ( J:76407 )

• proliferating zone of chondrocytes is reduced

abnormal long bone hypertrophic chondrocyte zone ( J:76407 )

• deposition of type X collagen in the matrix of the hypertrophic zone is increased

increased width of hypertrophic chondrocyte zone ( J:76407 )

• hypertrophic zone is enlarged

abnormal bone mineralization ( J:76407 )

• mineralization of cartilage matrix is enhanced

hematopoietic system

abnormal osteoclast morphology ( J:76407 )

• size of osteoclasts is decreased

decreased osteoclast cell number ( J:76407 )

immune system

abnormal osteoclast morphology ( J:76407 )

• size of osteoclasts is decreased

decreased osteoclast cell number ( J:76407 )

Genotype
MGI:3617819

ht5

• Allelic Composition: Pthlh^tm1Hmk/Pthlh⁺
• Genetic Background: involves: 129S2/SvPas

skeleton

abnormal osteoblast differentiation ( J:100918 )

• the number of osteoblastic cells formed from cultured bone marrow cells is severely decreased

abnormal osteoclast morphology ( J:100918 )

• osteoclast surface relative to bone surface is reduced

decreased osteoblast cell number ( J:100918 )

• increase in apoptotic osteoblastic cells

abnormal trabecular bone morphology ( J:100918 )

• the 3 dimensional structure of the trabecular bone is altered, trabecular separation is increased, and a 50% is seen in the bone volume/tissue volume ratio

• rather than the normal trabecular plates rodlike structures are present and the degree of anisotropy is decreased

abnormal bone ossification ( J:100918 )

• the mineral apposition rate is decreased in the metaphyseal trabecular bone

• injection of the 1-34 amino acid terminal fragment of human parathyroid hormone increases the mineral apposition rate relative to untreated heterozygotes

hematopoietic system

abnormal osteoclast morphology ( J:100918 )

• osteoclast surface relative to bone surface is reduced

immune system

abnormal osteoclast morphology ( J:100918 )

• osteoclast surface relative to bone surface is reduced

cellular

abnormal osteoblast differentiation ( J:100918 )

• the number of osteoblastic cells formed from cultured bone marrow cells is severely decreased

Genotype
MGI:3510232

ht6

• Allelic Composition: Pthlh^tm1Hmk/Pthlh⁺
• Genetic Background: involves: 129S2/SvPas * C57BL/6

skeleton

decreased long bone epiphyseal plate size ( J:99641 )

• growth plate is shorted by about 8%

Genotype
MGI:3617820

cn7

• Allelic Composition: Pthlh^tm1Ack/Pthlh^tm1Hmk; Tmem163^{Tg(ACTB-cre)2Mrt}/0
• Genetic Background: involves: 129 * BALB/c * FVB/N

mortality/aging

neonatal lethality, complete penetrance ( J:69396 )

skeleton

short mandible ( J:69396 )

domed cranium ( J:69396 )

abnormal long bone epiphyseal plate morphology ( J:69396 )

• the chondrocyte columns are disorganized and premature differentiation to the hypertrophic state occurs

abnormal long bone epiphyseal plate proliferative zone ( J:69396 )

• decreased in size

disorganized long bone epiphyseal plate ( J:69396 )

• the chondrocyte columns are disorganized

premature endochondral bone ossification ( J:69396 )

• premature and inappropriate ossification throughout the endochondral skeleton

respiratory system

respiratory failure ( J:69396 )

growth/size/body

protruding tongue ( J:69396 )

• shortening of the mandible results in protrusion of the tongue

small thoracic cavity ( J:69396 )

• narrow thorax

distended abdomen ( J:69396 )

craniofacial

short mandible ( J:69396 )

domed cranium ( J:69396 )

protruding tongue ( J:69396 )

• shortening of the mandible results in protrusion of the tongue

digestive/alimentary system

protruding tongue ( J:69396 )

• shortening of the mandible results in protrusion of the tongue

Genotype
MGI:3617822

cn8

• Allelic Composition: Pthlh^tm1Ack/Pthlh^tm1Hmk; Tg(LGB-cre)74Acl/0
• Genetic Background: involves: 129 * C57BL/6 * CBA

skeleton

abnormal osteoclast morphology ( J:86536 )

• the osteoclast surface/bone surface ratio and number of osteoclasts per bone perimeter are reduced

increased bone mass ( J:86536 )

• the reduced rate of bone turnover during lactation preserves bone mass so that on day 12 of lactation mutants have nearly 20% more bone mass than controls

• however, bone mass is similar to controls at the start of lactation

abnormal bone ossification ( J:86536 )

• bone formation rate per tissue volume is reduced

• however, osteoblast numbers and surface appear normal

homeostasis/metabolism

abnormal circulating hormone level ( J:86536 )

• plasma levels of parathyroid hormone related protein are significantly lower in lactating mutants compared to controls; however plasma levels of parathyroid hormone and calcium are normal

abnormal vitamin D level ( J:86536 )

• plasma levels of 1,25-dihydroxy vitamin D are significantly lower (43.5 +/- 2.2 pg/ml versus 55.9 +/- 5.9 pg/ml in controls)

abnormal urine homeostasis ( J:86536 )

• urinary excretion of cAMP is decreased to 19.3 +/- 0.8 ug/mmol creatinine compared to 33.9 +/- 0.6 ug/mmol creatinine in controls

• urinary levels of C-telopeptides of type I collagen are significantly lower (3.98 +/- 0.82 ug/mmol creatinine versus 6.83 +/- 0.29 ug/mmol creatinine in controls)

reproductive system

reproductive system phenotype ( J:86536 )

N • no functional defects in lactation, abnormalities in mammary gland morphology, or decrease in litter size or growth of pups is seen

renal/urinary system

abnormal urine homeostasis ( J:86536 )

• urinary excretion of cAMP is decreased to 19.3 +/- 0.8 ug/mmol creatinine compared to 33.9 +/- 0.6 ug/mmol creatinine in controls

• urinary levels of C-telopeptides of type I collagen are significantly lower (3.98 +/- 0.82 ug/mmol creatinine versus 6.83 +/- 0.29 ug/mmol creatinine in controls)

hematopoietic system

abnormal osteoclast morphology ( J:86536 )

• the osteoclast surface/bone surface ratio and number of osteoclasts per bone perimeter are reduced

immune system

abnormal osteoclast morphology ( J:86536 )

• the osteoclast surface/bone surface ratio and number of osteoclasts per bone perimeter are reduced

Genotype
MGI:3584345

cn9

• Allelic Composition: Pthlh^tm1Hmk/Pthlh⁺; Pth1r^tm1Hmk/Pth1r^tm2Hmk; Tg(Bglap2-cre)1Kry/0
• Genetic Background: involves: 129S2/SvPas * 129S4/SvJae * C57BL/6 * FVB/N

skeleton

decreased long bone epiphyseal plate size ( J:99641 )

• growth plate is shorted by about 8%

Genotype
MGI:3584347

cn10

• Allelic Composition: Pthlh^tm1Hmk/Pthlh^tm1Hmk; Pth1r^tm1Hmk/Pth1r^tm2Hmk; Tg(Bglap2-cre)1Kry/0; Tg(Col2a1-PTHLH)1Ecw/0
• Genetic Background: involves: 129S2/SvPas * 129S4/SvJae * C57BL/6 * FVB * SJL

skeleton

long tibia ( J:99641 )

• increase in tibia length

abnormal long bone epiphyseal plate morphology ( J:99641 )

• exhibit ectopically differentiated chondrocytes

abnormal chondrocyte differentiation ( J:99641 )

• eutopic hypertrophic chondrocyte differentiation is stimulated

limbs/digits/tail

long tibia ( J:99641 )

• increase in tibia length

Genotype
MGI:3584346

cx11

• Allelic Composition: Pthlh^tm1Hmk/Pthlh^tm1Hmk; Pth1r^tm1Hmk/Pth1r^tm2Hmk; Tg(Col2a1-PTHLH)1Ecw/0
• Genetic Background: involves: 129S2/SvPas * 129S4/SvJae * C57BL/6 * SJL

skeleton

short tibia ( J:99641 )

abnormal long bone epiphyseal plate morphology ( J:99641 )

• rescued growth plate lacks hypertrophic chondrocytes and columnar cells

abnormal bone ossification ( J:99641 )

• bone formation is suppressed

limbs/digits/tail

short tibia ( J:99641 )

immune system

abnormal bone marrow development ( J:99641 )

• bone marrow formation is suppressed

Genotype
MGI:3584031

cx12

• Allelic Composition: Pthlh^tm1Hmk/Pthlh^tm1Hmk; Tg(Col2a1-PTHR1*H223R)AHju/Tg(Col2a1-PTHR1*H223R)AHju
• Genetic Background: involves: 129S2/SvPas * C57BL/6

Histological tibiae sections of mice homozygous for Tg(Col2a1-PTHR1*H223R)AHju, mice homozygous for Tg(Col2a1-PTHR1*H223R)AHju and Pthlh^tm1Hmk and mice homozygous for Pthlh^tm1Hmk

mortality/aging

premature death ( J:77639 )

• survive up to 2 months compared to death around birth in single Pthlh homozygous null mice

growth/size/body

abnormal tooth morphology ( J:77639 )

abnormal odontoblast morphology ( J:77639 )

• the odontoblast layer is disorganized

abnormal ameloblast morphology ( J:77639 )

• number of ameloblasts is reduced

failure of tooth eruption ( J:77639 )

• tooth eruption is lacking even though tooth buds develop

abnormal postnatal growth ( J:77639 )

• although the endochondral bone formation defect of Pthlh homozygous null mice is rescued, mutant mice are malnourished and grow less than controls

skeleton

abnormal tooth morphology ( J:77639 )

abnormal odontoblast morphology ( J:77639 )

• the odontoblast layer is disorganized

abnormal ameloblast morphology ( J:77639 )

• number of ameloblasts is reduced

failure of tooth eruption ( J:77639 )

• tooth eruption is lacking even though tooth buds develop

abnormal long bone epiphyseal plate morphology ( J:77639 )

• premature disappearance of the growth plates and their secondary ossification centers

craniofacial

abnormal tooth morphology ( J:77639 )

abnormal odontoblast morphology ( J:77639 )

• the odontoblast layer is disorganized

abnormal ameloblast morphology ( J:77639 )

• number of ameloblasts is reduced

failure of tooth eruption ( J:77639 )

• tooth eruption is lacking even though tooth buds develop

Genotype
MGI:3584341

cx13

• Allelic Composition: Pthlh^tm1Hmk/Pthlh⁺; Tg(Col2a1-GAL4)1Amc/0; Tg(UAS-IHH)1Amc/0
• Genetic Background: involves: 129S2/SvPas * C57BL/6

skeleton

decreased long bone epiphyseal plate size ( J:99641 )

• growth plate is shorted by about 8%

Genotype
MGI:3584352

cx14

• Allelic Composition: Pthlh^tm1Hmk/Pthlh^tm1Hmk; Tg(Col2a1-GAL4)1Amc/0; Tg(Col2a1-PTHR1*H223R)AHju/?; Tg(UAS-IHH)1Amc/0
• Genetic Background: involves: 129S2/SvPas * C57BL/6

skeleton

abnormal long bone epiphyseal plate morphology ( J:99641 )

• increase in length of the columnar region compared to Pthlh mutant mice that express the constitutively active PTHR1 but do not overexpress IHH

Genotype
MGI:3717204

cx15

• Allelic Composition: Pthlh^tm1Hmk/Pthlh^tm1Hmk; Tg(Col2a1-PTHR1*H223R)AHju/0
• Genetic Background: involves: 129S2/SvPas * C57BL/6

Alizarin red S stained skeletal images of hemizygous and homozygous Tg(Col2a1-PTHR1*H223R)AHju and Pthlh^tm1Hmk/Pthlh^tm1Hmk mice

mortality/aging

premature death ( J:77639 )

• postnatal survival is prolonged for up to 2 months compared to death around birth in single Pthlh homozygous null mice

skeleton

skeleton phenotype ( J:77639 )

N • at birth or before birth, mutant skeletons appear normal and do not exhibit premature or abnormal mineralization, indicating rescue by the transgene

abnormal long bone hypertrophic chondrocyte zone ( J:99641 )

• growth plate of the distal tibia at E17.5 shows relatively normal appearance except for mild shortening of the columnar region and delayed blood vessel invasion

Genotype
MGI:2665233

cx16

• Allelic Composition: Pth^tm1Dgo/Pth^tm1Dgo; Pthlh^tm1Hmk/Pthlh^tm1Hmk
• Genetic Background: involves: 129S2/SvPas * C57BL/6J

Skeletal phenotypes and tibial histology of Pth^tm1Dgo/Pth^tm1Dgo, Pthlh^tm1Hmk/Pthlh^tm1Hmk and Pth^tm1Dgo/Pth^tm1Dgo Pthlh^tm1Hmk/Pthlh^tm1Hmk mice

cellular

increased chondrocyte apoptosis ( J:76407 )

• number of apoptotic chondrocytes is increased five-fold

increased osteoblast apoptosis ( J:76407 )

• increase in osteoblast apoptosis in the endosteum

increased osteocyte apoptosis ( J:76407 )

• increase in levels of apoptosis in osteocytes in the endosteum

mortality/aging

perinatal lethality, complete penetrance ( J:76407 )

• mutants die at birth

growth/size/body

disproportionate dwarf ( J:76407 )

• short limbed dwarfism

endocrine/exocrine glands

enlarged parathyroid gland ( J:76407 )

• parathyroid glands are even more enlarged than in single Pth homozygotes

skeleton

increased chondrocyte apoptosis ( J:76407 )

• number of apoptotic chondrocytes is increased five-fold

increased osteoblast apoptosis ( J:76407 )

• increase in osteoblast apoptosis in the endosteum

increased osteocyte apoptosis ( J:76407 )

• increase in levels of apoptosis in osteocytes in the endosteum

abnormal skeleton morphology ( J:76407 )

• all elements of the axial and appendicular skeletons are dramatically reduced in size

abnormal appendicular skeleton morphology ( J:76407 )

• all elements of the appendicular skeleton are dramatically reduced in size

decreased length of long bones ( J:76407 )

abnormal axial skeleton morphology ( J:76407 )

• all elements of the axial skeleton are dramatically reduced in size

abnormal bone structure ( J:76407 )

abnormal osteoclast morphology ( J:76407 )

• size of osteoclasts is decreased

decreased osteoclast cell number ( J:76407 )

increased compact bone thickness ( J:76407 )

decreased osteoblast cell number ( J:76407 )

• decrease in osteoblast numbers in the primary spongiosa and in the endosteum

abnormal trabecular bone morphology ( J:76407 )

• trabecular bone volume is diminished

abnormal cartilage development ( J:76407 )

• reduction in cartilage matrix mineralization

abnormal long bone epiphyseal plate proliferative zone ( J:76407 )

• proliferating zone of chondrocytes is reduced

abnormal long bone hypertrophic chondrocyte zone ( J:76407 )

• deposition of type X collagen in the matrix of the hypertrophic zone is increased

increased width of hypertrophic chondrocyte zone ( J:76407 )

• hypertrophic zone is enlarged

abnormal bone mineralization ( J:76407 )

• mineralization of cartilage matrix is reduced

limbs/digits/tail

short limbs ( J:76407 )

cardiovascular system

abnormal angiogenesis ( J:76407 )

• vascular invasion in the growth plate is reduced

hematopoietic system

abnormal osteoclast morphology ( J:76407 )

• size of osteoclasts is decreased

decreased osteoclast cell number ( J:76407 )

immune system

abnormal osteoclast morphology ( J:76407 )

• size of osteoclasts is decreased

decreased osteoclast cell number ( J:76407 )

Genotype
MGI:3717420

cx17

• Allelic Composition: Pthlh^tm1Hmk/Pthlh^tm1Hmk; Tg(Col2a1-PTHLH)2Ecw/0; Tg(KRT14-PTHLH)7Wmp/0
• Genetic Background: involves: 129S2/SvPas * C57BL/6 * SJL

Dental phenotype of Pthlh^tm1Hmk/Pthlh^tm1Hmk mice rescued with Tg(Col2a1-PTHLH)2Ecw and Tg(KRT14-PTHLH)7Wmp transgenes

mortality/aging

premature death ( J:50144 )

growth/size/body

long lower incisors ( J:50144 )

• malocclusion allows for unchecked growth of the lower incisors

malocclusion ( J:50144 )

• as a result of the chondrodystrophy in the skulls, the lower mandibular incisors protrude beyond the upper incisors

• upper incisors remain partly occluded and are less affected

• however, incisors and molars erupt normally and on schedule

decreased body size ( J:50144 )

decreased body weight ( J:50144 )

skeleton

long lower incisors ( J:50144 )

• malocclusion allows for unchecked growth of the lower incisors

malocclusion ( J:50144 )

• as a result of the chondrodystrophy in the skulls, the lower mandibular incisors protrude beyond the upper incisors

• upper incisors remain partly occluded and are less affected

• however, incisors and molars erupt normally and on schedule

short maxilla ( J:50144 )

• foreshortened maxilla

chondrodystrophy ( J:50144 )

• develop progressive chondrodystrophy

craniofacial

long lower incisors ( J:50144 )

• malocclusion allows for unchecked growth of the lower incisors

malocclusion ( J:50144 )

• as a result of the chondrodystrophy in the skulls, the lower mandibular incisors protrude beyond the upper incisors

• upper incisors remain partly occluded and are less affected

• however, incisors and molars erupt normally and on schedule

short maxilla ( J:50144 )

• foreshortened maxilla

Genotype
MGI:3717417

cx18

• Allelic Composition: Pthlh^tm1Hmk/Pthlh^tm1Hmk; Tg(Col2a1-PTHLH)2Ecw/0
• Genetic Background: involves: 129S2/SvPas * C57BL/6 * SJL

Skeletal phenotypes of wild type, Tg(Col2a1-PTHLH)2Ecw/0, Pthlh^tm1Hmk/Pthlh^tm1Hmk, and Pthlh^tm1Hmk/Pthlh^tm1Hmk Tg(Col2a1-PTHLH)2Ecw/0 mice

mortality/aging

premature death ( J:50144 )

• life span of the rest is about 6 months

postnatal lethality, incomplete penetrance ( J:50144 )

• less than half survive past 3 weeks of age

growth/size/body

frontal bossing ( J:50144 )

abnormal molar morphology ( J:50144 )

• the molar crypt is choked with bone and the teeth are distorted, however the ameloblast layer is intact and the enamel is deposited

abnormal tooth development ( J:50144 )

• tooth morphogenesis is normal in late gestation but by birth, incisors are impacted and by 1 week of age, the molars are also impacted

failure of tooth eruption ( J:50144 )

• failure of tooth eruption leading to the absence of external incisors and molars

tooth impaction ( J:50144 )

• incisors and molars are impacted

tooth ankylosis ( J:50144 )

• teeth become irreversibly ankylosed because of the fusion of the dental cementum with the encroaching alveolar bone

abnormal enamel morphology ( J:50144 )

• enamel is absent from the labial surface of the incisor

abnormal ameloblast morphology ( J:50144 )

• the ameloblast layer of incisors is missing

absent tooth root ( J:50144 )

• failure of root formation

flattened snout ( J:50144 )

decreased body size ( J:50144 )

• mutants fail to thrive and exhibit a 50% reduction in both size and weight by the time of weaning

disproportionate dwarf ( J:50144 )

• with increasing age, display a progressive short-limbed dwarfism

limbs/digits/tail

short limbs ( J:50144 )

• foreshortening of the limbs is apparent by 8 weeks of age

vision/eye

shallow orbits ( J:50144 )

• shallow eye sockets

exophthalmos ( J:50144 )

• shallow eye sockets cause ocular proptosis

craniofacial

abnormal neurocranium morphology ( J:50144 )

• with increasing age, display doming of the calvarium

frontal bossing ( J:50144 )

shallow orbits ( J:50144 )

• shallow eye sockets

abnormal molar morphology ( J:50144 )

• the molar crypt is choked with bone and the teeth are distorted, however the ameloblast layer is intact and the enamel is deposited

abnormal tooth development ( J:50144 )

• tooth morphogenesis is normal in late gestation but by birth, incisors are impacted and by 1 week of age, the molars are also impacted

failure of tooth eruption ( J:50144 )

• failure of tooth eruption leading to the absence of external incisors and molars

tooth impaction ( J:50144 )

• incisors and molars are impacted

tooth ankylosis ( J:50144 )

• teeth become irreversibly ankylosed because of the fusion of the dental cementum with the encroaching alveolar bone

abnormal enamel morphology ( J:50144 )

• enamel is absent from the labial surface of the incisor

abnormal ameloblast morphology ( J:50144 )

• the ameloblast layer of incisors is missing

absent tooth root ( J:50144 )

• failure of root formation

short mandible ( J:50144 )

• foreshortened mandible

short maxilla ( J:50144 )

• foreshortened maxilla

flattened snout ( J:50144 )

skeleton

abnormal neurocranium morphology ( J:50144 )

• with increasing age, display doming of the calvarium

frontal bossing ( J:50144 )

shallow orbits ( J:50144 )

• shallow eye sockets

abnormal molar morphology ( J:50144 )

• the molar crypt is choked with bone and the teeth are distorted, however the ameloblast layer is intact and the enamel is deposited

abnormal tooth development ( J:50144 )

• tooth morphogenesis is normal in late gestation but by birth, incisors are impacted and by 1 week of age, the molars are also impacted

failure of tooth eruption ( J:50144 )

• failure of tooth eruption leading to the absence of external incisors and molars

tooth impaction ( J:50144 )

• incisors and molars are impacted

tooth ankylosis ( J:50144 )

• teeth become irreversibly ankylosed because of the fusion of the dental cementum with the encroaching alveolar bone

abnormal enamel morphology ( J:50144 )

• enamel is absent from the labial surface of the incisor

abnormal ameloblast morphology ( J:50144 )

• the ameloblast layer of incisors is missing

absent tooth root ( J:50144 )

• failure of root formation

short mandible ( J:50144 )

• foreshortened mandible

short maxilla ( J:50144 )

• foreshortened maxilla

chondrodystrophy ( J:50144 )

• cranial chondrodystrophy includes doming of the calvarium, frontal bossing, and a flattened snout