Mouse Genome Informatics
hm1
    Prkacatm1Gsm/Prkacatm1Gsm
involves: 129X1/SvJ * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• influenced by genetic background, with decreased survival associated with increased C57BL/6 contribution
• some mice surviving past weaning

growth/size
• 35% reduction in weight at 3 months of age relative to wild-type littermates
• beginning at 2 weeks of age (J:77110)
• normal serum levels of growth hormone (GH) though mice were partially GH resistant (J:77110)

homeostasis/metabolism
• reduction in the levels of major urinary proteins

renal/urinary system
• reduction in the levels of major urinary proteins

reproductive system
N
• full spectrum of male gametes observed indicating normal spermatogenesis (J:77110)
• normal testicular weight (J:77110)
• normal sperm count (J:77110)
(J:76765)
• reduced forward velocity (J:77110)


Mouse Genome Informatics
ht2
    Prkacatm1Gsm/Prkaca+
involves: 129X1/SvJ * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
skeleton
• trabecular bone is decreased
• mutants exhibit overall gain in bone formation derived from primarily cortical bone


Mouse Genome Informatics
cx3
    Prkacatm1Gsm/Prkaca+
Prkar1atm1.1Lsk/Prkar1a+

involves: 129S1/Sv * 129X1/SvJ * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
tumorigenesis
N
• mutants do not develop schwannomas or thyroid tumors (J:160299)
• mutants develop a greater number of osseous lesions and develop them earlier than single Prkar1a heterozygotes (J:160299)
• 90% of mutants exhibit bone lesions in the tail by 6 months and 100% by 9 months of age (J:160299)
• osseous lesions are seen starting around 3 months of age and vary from rare chondromas in the long bones and ubiquitous osteochondrodysplasia of vertebral bodies to occasional sarcoma (J:160299)
• 13% of mutants develop osteochondromyoxoma (J:160299)
• cells from the bone lesions originate from an area proximal to the growth plate (J:160299)
• cartilaginous metaplasia, chondromas, and osteochondrodysplasia are seen in marrow cavities of up to 1/3 of the long bones and most of the vertebral bodies (J:160299)
• lesions are hypercellular and contain more irregular cartilage or bone islands; proliferating cells are committed osteogenic but are not able to mature into osteoblasts (J:160299)
• mutants develop bone tumors with histological resemblance to those seen in humans with neonatal-onset multisystem inflammatory disease, with lesions derived from osteoblast progenitor cells (J:166728)
• rare development of metastatic osteochondrosarcomas
• rare chondromas in the long bones

skeleton
• overall bone mineralization density is lower than in wild-type mice
• in affected bones, normal cortical bone is replaced by mineralized material
• periosteum of affected bones is abnormal, with occasional cells from lesions crossing the periosteum into the extraosseous space and Sharpey fibers, characteristic of fibrous dysplasia, are observed
• although the bone marrow is expanded by active osteoclastic activity, these cells are not able to mature into osteoblasts and mineralize the matrix resulting in undermineralization
• bones exhibit a lag between bone matrix formation and mineralization and abnormal coordination of these processes with bone resorption

Mouse Models of Human Disease
OMIM IDRef(s)
CINCA Syndrome; CINCA 607115 J:166728


Mouse Genome Informatics
cx4
    Prkacatm1Gsm/Prkacatm1Gsm
Prkar1atm1Gsm/Prkar1atm1Gsm

involves: 129X1/SvJ * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• E10.5 embryos exhibit an expanded fluid-filled pericardial cavity, even though exhibit rescue of the other phenotypes seen in Prkar1a null mice (develop a heart tube, undergo embryo turning, etc)

homeostasis/metabolism
• E10.5 embryos exhibit an expanded fluid-filled pericardial cavity, even though exhibit rescue of the other phenotypes seen in Prkar1a null mice (develop a heart tube, undergo embryo turning, etc)


Mouse Genome Informatics
cx5
    Prkacatm1Gsm/Prkaca+
Prkacbtm1Gsm/Prkacbtm1Gsm

involves: 129X1/SvJ * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Neural tube defects leading to spina bifida in Prkacatm1Gsm/Prkaca+ Prkacbtm1Gsm/Prkacbtm1Gsm and Prkacatm1Gsm/Prkacatm1Gsm Prkacbtm1Gsm/Prkacb+ mice

mortality/aging
• if mutant pups are kept with their parents, they are rejected and left out of the litter and die, probably from starvation

nervous system
• 100% show spinal neural tube defects
• E9.5-10.5 embryos exhibit a closed neural tube with an expanded alar plate and enlarged lumen in the thoracic and lumbar regions and an expanded neuroepithelium
• E10.5 or older embryos show a drastic increase in the expansion of the neural canal (enlarged lumen) and a neuroepithelium with a higher cell density
• E9.5-E10.5 embryos exhibit an expanded neuroepithelium with a higher cell density
• at the thoracic and lumbar regions
• altered neuronal identity in the neural tube posterior to the forelimb buds leading to a ventralized neural tube (appearance of ventral neuronal progenitors in the dorsal neural tube and loss of dorsal cell types)
• dorsal root ganglia form in E10.5 embryos but regress at E12.5
• significant increase in cell death in the dorsal root ganglia adjacent to the affected neural tube
• dorsal root ganglia are formed in E10.5 embryos but are disorganized
• increase in apoptotic cells in the dorsal and lateral regions of the neural tube

skeleton
• spinal column defects are located in the thoracic and lumbar regions
• ventral curvature of the spine at the defective region
• vertebral arches fail to fuse at the dorsal midline between forelimbs and hindlimbs

embryogenesis
• 100% show spinal neural tube defects
• E9.5-10.5 embryos exhibit a closed neural tube with an expanded alar plate and enlarged lumen in the thoracic and lumbar regions and an expanded neuroepithelium
• E10.5 or older embryos show a drastic increase in the expansion of the neural canal (enlarged lumen) and a neuroepithelium with a higher cell density
• E9.5-E10.5 embryos exhibit an expanded neuroepithelium with a higher cell density
• at the thoracic and lumbar regions


Mouse Genome Informatics
cx6
    Prkacatm1Gsm/Prkacatm1Gsm
Prkacbtm1Gsm/Prkacb+

involves: 129X1/SvJ * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Neural tube defects leading to spina bifida in Prkacatm1Gsm/Prkaca+ Prkacbtm1Gsm/Prkacbtm1Gsm and Prkacatm1Gsm/Prkacatm1Gsm Prkacbtm1Gsm/Prkacb+ mice

mortality/aging

nervous system
• 75% show spinal neural tube defects
• 25% show spinal neural tube defects and exencephaly
• E9.5-10.5 embryos exhibit a closed neural tube with an expanded alar plate and enlarged lumen in the thoracic and lumbar regions and an expanded neuroepithelium
• E10.5 or older embryos show a drastic increase in the expansion of the neural canal (enlarged lumen) and a neuroepithelium with a higher cell density
• exhibit an increase in apoptotic cells in the dorsal and lateral regions of the neural tube
• E9.5-E10.5 embryos exhibit an expanded neuroepithelium with a higher cell density
• at the thoracic and lumbar regions
• 25% show spinal neural tube defects and exencephaly; exencephaly alone is not observed
• altered neuronal identity in the neural tube posterior to the forelimb buds leading to a ventralized neural tube (appearance of ventral neuronal progenitors in the dorsal neural tube and loss of dorsal cell types)
• dorsal root ganglia form in E10.5 embryos but regress at E12.5
• significant increase in cell death in the dorsal root ganglia adjacent to the affected neural tube
• dorsal root ganglia are formed in E10.5 embryos but are disorganized

skeleton
• spinal column defects are located in the thoracic and lumbar regions
• ventral curvature of the spine at the defective region
• vertebral arches fail to fuse at the dorsal midline between forelimbs and hindlimbs

embryogenesis
• 75% show spinal neural tube defects
• 25% show spinal neural tube defects and exencephaly
• E9.5-10.5 embryos exhibit a closed neural tube with an expanded alar plate and enlarged lumen in the thoracic and lumbar regions and an expanded neuroepithelium
• E10.5 or older embryos show a drastic increase in the expansion of the neural canal (enlarged lumen) and a neuroepithelium with a higher cell density
• exhibit an increase in apoptotic cells in the dorsal and lateral regions of the neural tube
• E9.5-E10.5 embryos exhibit an expanded neuroepithelium with a higher cell density
• at the thoracic and lumbar regions


Mouse Genome Informatics
cx7
    Prkacatm1Gsm/Prkacatm1Gsm
Prkacbtm1Gsm/Prkacbtm1Gsm

involves: 129X1/SvJ * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• all double mutants found at E8.5 to E10.5 are in various stages of resorption, indicating early embryonic lethality