Mouse Genome Informatics
hm1
    Pthlhtm1Hmk/Pthlhtm1Hmk
either: (involves: 129S2/SvPas) or (involves: 129S2/SvPas * C57BL/6)
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mice die immediately after birth

respiratory system
• mice make feeble attempts to breathe

homeostasis/metabolism
• skin remains bluish-grey until death

skeleton
• long bones are shorter, thicker, and deformed with mildy splayed ends
• irregular metaphyseal margins in the long bones
• the thoracic cage is narrow and bell-shaped
• smaller in height and exhibit advanced ossification involving both the vertebral bodies and the articular processes
• bony trabeculae of the primary spongiosa are shortened and distorted
• zone of resting chondrocytes and the zones of proliferation and maturation are shortened, however the numbers of multinucleated chondroclasts and osteoclasts are normal
• columns of proliferating chondrocytes are shorter and irregularly arranged
• cartilage primorida of the ulna and radious are deformed and shortened at E14.5 but not at E12.5
• exhibit osteochondrodysplasia
• excessive/advanced mineralization
• exhibit acceleration of the normal endochondral ossification process and also abnormal maturation of hyaline rib chondrocytes with associated perichondral ossification

limbs/digits/tail

craniofacial

digestive/alimentary system

growth/size/body

Mouse Models of Human Disease
OMIM IDRef(s)
Achondroplasia; ACH 100800 J:16911


Mouse Genome Informatics
hm2
    Pthlhtm1Hmk/Pthlhtm1Hmk
involves: 129S2/SvPas
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Skeletal phenotypes of wild type, Tg(Col2a1-PTHLH)2Ecw/0, Pthlhtm1Hmk/Pthlhtm1Hmk, and Pthlhtm1Hmk/Pthlhtm1Hmk Tg(Col2a1-PTHLH)2Ecw/0 mice

skeleton
• inappropriate ossification of the costal cartilage and along the length of the sternum
• accelerated mineralization of the endochondral bones of the cranial base


Mouse Genome Informatics
hm3
    Pthlhtm1Hmk/Pthlhtm1Hmk
involves: 129S2/SvPas * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Alizarin red S stained skeletal images of hemizygous and homozygous Tg(Col2a1-PTHR1*H223R)AHju and Pthlhtm1Hmk/Pthlhtm1Hmk mice

mortality/aging
• mice die at birth due to respiratory failure

respiratory system
• at E18.5 and at term (E19.0?E19.5), mutant lungs are denser and less-well aerated than control lungs
• 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
• 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
• 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
• at E18.5, the mean area per saccule is reduced by ~50%
• at E18.5, the septal mesenchyme displays an abnormal thickness and cellularity that is typical of canalicular-stage lung
• at E18.5, the cuboidal epithelium shows a significantly greater nuclear:cell area ratio
• at E18.5, thin type I-like epithelial cells are absent, unlike in wild-type lungs
• 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
• at E18.5, few precursor multilamellar inclusion bodies or mature lamellar bodies are observed
• 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
• at E18.5 and at term, mutant lungs are smaller than control lungs
• however, lung weights are not significantly altered
• mice die at birth due to respiratory failure
• 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
• lungs removed from spontaneously delivered mice fail to float in saline solution

skeleton
• deformed long bones
• diminished height of growth plate cartilage
• premature ossification of the synchondrosis between the basoccipital bone and the basisphenoid bone

craniofacial

growth/size/body
• at E18.5, thoracic volume is reduced by >50%

cellular
• 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


Mouse Genome Informatics
hm4
    Pthlhtm1Hmk/Pthlhtm1Hmk
involves: 129S2/SvPas * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Skeletal phenotypes and tibial histology of Pthtm1Dgo/Pthtm1Dgo, Pthlhtm1Hmk/Pthlhtm1Hmk and Pthtm1Dgo/Pthtm1Dgo Pthlhtm1Hmk/Pthlhtm1Hmk mice

mortality/aging
• mutants die at birth

growth/size/body
• short limbed dwarfism

endocrine/exocrine glands
• moderately enlarged

limbs/digits/tail

skeleton
• size of osteoclasts is decreased
• increase in osteoblast and osteocyte apoptosis in the endosteum
• increase in osteoblast numbers in the primary spongiosa and in the endosteum
• increase in levels of apoptosis in osteocytes in the endosteum
• trabecular bone volume is somewhat increased
• reduction in cartilage mineralization
• proliferating zone of chondrocytes is reduced
• deposition of type X collagen in the matrix of the hypertrophic zone is increased
• hypertrophic zone is enlarged
• number of apoptotic chondrocytes is increased five-fold
• mineralization of cartilage matrix is enhanced

hematopoietic system
• size of osteoclasts is decreased

immune system
• size of osteoclasts is decreased


Mouse Genome Informatics
ht5
    Pthlhtm1Hmk/Pthlh+
involves: 129S2/SvPas
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
skeleton
• the number of osteoblastic cells formed from cultured bone marrow cells is severely decreased
• osteoclast surface relative to bone surface is reduced
• increase in apoptotic osteoblastic cells
• 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
• 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
• osteoclast surface relative to bone surface is reduced

immune system
• osteoclast surface relative to bone surface is reduced

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


Mouse Genome Informatics
ht6
    Pthlhtm1Hmk/Pthlh+
involves: 129S2/SvPas * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
skeleton
• growth plate is shorted by about 8%


Mouse Genome Informatics
cn7
    Pthlhtm1Ack/Pthlhtm1Hmk
Tg(ACTB-cre)2Mrt/0

involves: 129 * BALB/c * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging

skeleton
• the chondrocyte columns are disorganized and premature differentiation to the hypertrophic state occurs
• the chondrocyte columns are disorganized
• premature and inappropriate ossification throughout the endochondral skeleton

respiratory system

growth/size/body
• shortening of the mandible results in protrusion of the tongue
• narrow thorax

craniofacial
• shortening of the mandible results in protrusion of the tongue

digestive/alimentary system
• shortening of the mandible results in protrusion of the tongue


Mouse Genome Informatics
cn8
    Pthlhtm1Ack/Pthlhtm1Hmk
Tg(LGB-cre)74Acl/0

involves: 129 * C57BL/6 * CBA
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
skeleton
• the osteoclast surface/bone surface ratio and number of osteoclasts per bone perimeter are reduced
• 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
• bone formation rate per tissue volume is reduced
• however, osteoblast numbers and surface appear normal

homeostasis/metabolism
• 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
• 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)
• 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
N
• no functional defects in lactation, abnormalities in mammary gland morphology, or decrease in litter size or growth of pups is seen (J:86536)

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

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


Mouse Genome Informatics
cn9
    Pthlhtm1Hmk/Pthlh+
Pth1rtm1Hmk/Pth1rtm2Hmk
Tg(Bglap2-cre)1Kry/0

involves: 129S2/SvPas * 129S4/SvJae * C57BL/6 * FVB
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
skeleton
• growth plate is shorted by about 8%


Mouse Genome Informatics
cn10
    Pthlhtm1Hmk/Pthlhtm1Hmk
Pth1rtm1Hmk/Pth1rtm2Hmk
Tg(Bglap2-cre)1Kry/0
Tg(Col2a1-PTHLH)1Ecw/0

involves: 129S2/SvPas * 129S4/SvJae * C57BL/6 * FVB * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
skeleton
• increase in tibia length
• exhibit ectopically differentiated chondrocytes
• eutopic hypertrophic chondrocyte differentiation is stimulated

limbs/digits/tail
• increase in tibia length


Mouse Genome Informatics
cx11
    Pthlhtm1Hmk/Pthlhtm1Hmk
Pth1rtm1Hmk/Pth1rtm2Hmk
Tg(Col2a1-PTHLH)1Ecw/0

involves: 129S2/SvPas * 129S4/SvJae * C57BL/6 * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
skeleton
• rescued growth plate lacks hypertrophic chondrocytes and columnar cells
• bone marrow formation is suppressed
• bone formation is suppressed

limbs/digits/tail


Mouse Genome Informatics
cx12
    Pthlhtm1Hmk/Pthlhtm1Hmk
Tg(Col2a1-PTHR1*H223R)AHju/Tg(Col2a1-PTHR1*H223R)AHju

involves: 129S2/SvPas * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Histological tibiae sections of mice homozygous for Tg(Col2a1-PTHR1*H223R)AHju, mice homozygous for Tg(Col2a1-PTHR1*H223R)AHju and Pthlhtm1Hmk and mice homozygous for Pthlhtm1Hmk

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

growth/size/body
• number of ameloblasts is reduced
• tooth eruption is lacking even though tooth buds develop
• the odontoblast layer is disorganized
• although the endochondral bone formation defect of Pthlh homozygous null mice is rescued, mutant mice are malnourished and grow less than controls

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

craniofacial
• number of ameloblasts is reduced
• tooth eruption is lacking even though tooth buds develop
• the odontoblast layer is disorganized


Mouse Genome Informatics
cx13
    Pthlhtm1Hmk/Pthlh+
Tg(Col2a1-GAL4)1Amc/0
Tg(UAS-IHH)1Amc/0

involves: 129S2/SvPas * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
skeleton
• growth plate is shorted by about 8%


Mouse Genome Informatics
cx14
    Pthlhtm1Hmk/Pthlhtm1Hmk
Tg(Col2a1-GAL4)1Amc/0
Tg(Col2a1-PTHR1*H223R)AHju/?
Tg(UAS-IHH)1Amc/0

involves: 129S2/SvPas * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
skeleton
• increase in length of the columnar region compared to Pthlh mutant mice that express the constitutively active PTHR1 but do not overexpress IHH


Mouse Genome Informatics
cx15
    Pthlhtm1Hmk/Pthlhtm1Hmk
Tg(Col2a1-PTHR1*H223R)AHju/0

involves: 129S2/SvPas * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Alizarin red S stained skeletal images of hemizygous and homozygous Tg(Col2a1-PTHR1*H223R)AHju and Pthlhtm1Hmk/Pthlhtm1Hmk mice

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

skeleton
N
• at birth or before birth, mutant skeletons appear normal and do not exhibit premature or abnormal mineralization, indicating rescue by the transgene (J:77639)
• 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


Mouse Genome Informatics
cx16
    Pthlhtm1Hmk/Pthlhtm1Hmk
Tg(Col2a1-PTHLH)2Ecw/0

involves: 129S2/SvPas * C57BL/6 * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Skeletal phenotypes of wild type, Tg(Col2a1-PTHLH)2Ecw/0, Pthlhtm1Hmk/Pthlhtm1Hmk, and Pthlhtm1Hmk/Pthlhtm1Hmk Tg(Col2a1-PTHLH)2Ecw/0 mice

mortality/aging
• less than half survive past 3 weeks of age
• life span of the rest is about 6 months

growth/size/body
• teeth become irreversibly ankylosed because of the fusion of the dental cementum with the encroaching alveolar bone
• failure of root formation
• tooth morphogenesis is normal in late gestation but by birth, incisors are impacted and by 1 week of age, the molars are also impacted
• the ameloblast layer of incisors is missing
• the molar crypt is choked with bone and the teeth are distorted, however the ameloblast layer is intact and the enamel is deposited
• failure of tooth eruption leading to the absence of external incisors and molars
• incisors and molars are impacted
• enamel is absent from the labial surface of the incisor
• mutants fail to thrive and exhibit a 50% reduction in both size and weight by the time of weaning
• with increasing age, display a progressive short-limbed dwarfism

limbs/digits/tail
• foreshortening of the limbs is apparent by 8 weeks of age

vision/eye
• shallow eye sockets cause ocular proptosis

craniofacial
• with increasing age, display doming of the calvarium
• foreshortened mandible
• foreshortened maxilla
• teeth become irreversibly ankylosed because of the fusion of the dental cementum with the encroaching alveolar bone
• failure of root formation
• tooth morphogenesis is normal in late gestation but by birth, incisors are impacted and by 1 week of age, the molars are also impacted
• the ameloblast layer of incisors is missing
• the molar crypt is choked with bone and the teeth are distorted, however the ameloblast layer is intact and the enamel is deposited
• failure of tooth eruption leading to the absence of external incisors and molars
• incisors and molars are impacted
• enamel is absent from the labial surface of the incisor

skeleton
• with increasing age, display doming of the calvarium
• foreshortened mandible
• foreshortened maxilla
• cranial chondrodystrophy includes doming of the calvarium, frontal bossing, and a flattened snout


Mouse Genome Informatics
cx17
    Pthlhtm1Hmk/Pthlhtm1Hmk
Tg(Col2a1-PTHLH)2Ecw/0
Tg(PTHLH)7Wmp/0

involves: 129S2/SvPas * C57BL/6 * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Dental phenotype of Pthlhtm1Hmk/Pthlhtm1Hmk mice rescued with Tg(Col2a1-PTHLH)2Ecw and Tg(PTHLH)7Wmp transgenes

mortality/aging

growth/size/body
• malocclusion allows for unchecked growth of the lower incisors

skeleton
• foreshortened maxilla
• 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
• develop progressive chondrodystrophy

craniofacial
• foreshortened maxilla
• 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
• malocclusion allows for unchecked growth of the lower incisors


Mouse Genome Informatics
cx18
    Pthtm1Dgo/Pthtm1Dgo
Pthlhtm1Hmk/Pthlhtm1Hmk

involves: 129S2/SvPas * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Skeletal phenotypes and tibial histology of Pthtm1Dgo/Pthtm1Dgo, Pthlhtm1Hmk/Pthlhtm1Hmk and Pthtm1Dgo/Pthtm1Dgo Pthlhtm1Hmk/Pthlhtm1Hmk mice

mortality/aging
• mutants die at birth

growth/size/body
• short limbed dwarfism

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

skeleton
• all elements of the axial and appendicular skeletons are dramatically reduced in size
• all elements of the appendicular skeleton are dramatically reduced in size
• all elements of the axial skeleton are dramatically reduced in size
• size of osteoclasts is decreased
• increase in osteoblast and osteocyte apoptosis in the endosteum
• decrease in osteoblast numbers in the primary spongiosa and in the endosteum
• increase in levels of apoptosis in osteocytes in the endosteum
• trabecular bone volume is diminished
• reduction in cartilage matrix mineralization
• proliferating zone of chondrocytes is reduced
• deposition of type X collagen in the matrix of the hypertrophic zone is increased
• hypertrophic zone is enlarged
• number of apoptotic chondrocytes is increased five-fold
• mineralization of cartilage matrix is reduced

limbs/digits/tail

cardiovascular system
• vascular invasion in the growth plate is reduced

hematopoietic system
• size of osteoclasts is decreased

immune system
• size of osteoclasts is decreased