Phenotypes Associated with This Genotype

Genotype
MGI:5547618

• Allelic Composition: Tg(CKMM-tTA)A3Rhvh/0; Tg(tetO-H2-K1)#Papl/0
• Genetic Background: B6.Cg-Tg(CKMM-tTA)A3Rhvh Tg(tetO-H2-K1)#Papl

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

mortality/aging

mortality/aging ( J:205907 )

N • double mutants are born at the expected Mendelian ratio when mothers are treated with doxycycline to suppress H2-K1 expression

perinatal lethality, complete penetrance ( J:205907 )

• in the absence of doxycycline, no pups are seen, although mutants are identified among live 18-day embryos and several mummified mutant fetuses are retained in the uterus, suggesting parturition problems

growth/size/body

decreased body weight ( J:205907 )

♀ • females in which doxycycline is removed at 4 weeks of age show a 40-50% reduction in body weight at 6 months of age

cachexia ( J:205907 )

♀ • females in which doxycycline is removed at 4 weeks of age show arched spine, lower back and hind limb weakness and wasting becomes severe by 5-7 months of age

behavior/neurological

decreased locomotor activity ( J:205907 )

♀ • females in which doxycycline is removed at 4 weeks of age show a reduction in locomotor activity in an open field as early as 1 month after doxycycline removal and is striking by 5-7 months of age

muscle

myositis ( J:205907 )

• females in which doxycycline is removed at 4 weeks of age show macrophage infiltration in skeletal muscle by 3.5 months of age and mononuclear cell infiltration and invasion of some muscle fibers by phagocytes by 5.5 months of age

• males remain free of symptoms up to 5 months of age, but they all develop symptoms after 7 months of age

• administration of doxycycline at 4 months of age after the establishment of clinical disease for 5 months, fails to reverse the disease

abnormal skeletal muscle morphology ( J:205907 )

♀ • females in which doxycycline is removed at 4 weeks of age exhibit abnormal skeletal muscles with centralized nuclei, muscle fiber degeneration, and macrophage infiltration by 3.5 months of age and by 5.5 months, there is structural damage, showing centralized nuclei, variation in muscle fiber diameter, muscle fiber degeneration and regeneration, atrophy, obliteration of the striations of the contractile apparatus, mononuclear cell infiltration, and the invasion of some muscle fibers by phagocytes

skeletal muscle fiber atrophy ( J:205907 )

♀ • females in which doxycycline is removed at 4 weeks of age show muscle fiber atrophy by 5.5 months of age

skeletal muscle fiber degeneration ( J:205907 )

♀ • females in which doxycycline is removed at 4 weeks of age show muscle fiber degeneration by 3.5 months of age

muscle weakness ( J:205907 )

♀ • females develop signs of muscle weakness at about 3 months of age (2 months after transgene induction by doxycycline removal)

immune system

abnormal cytokine level ( J:205907 )

♀ • MIP1-alpha, MCP-1, and IL-15 are increased in muscle tissues of females in which doxycycline is removed at 4 weeks of age

increased autoantibody level ( J:205907 )

♀ • 8 of 23 mutants females in which doxycycline is removed at 4 weeks of age show elevated autoantibodies to histidyl-tRNA synthetase

increased anti-nuclear antigen antibody level ( J:205907 )

♀ • 5 of 18 females in which doxycycline is removed at 4 weeks of age show antinuclear antibodies

myositis ( J:205907 )

• females in which doxycycline is removed at 4 weeks of age show macrophage infiltration in skeletal muscle by 3.5 months of age and mononuclear cell infiltration and invasion of some muscle fibers by phagocytes by 5.5 months of age

• males remain free of symptoms up to 5 months of age, but they all develop symptoms after 7 months of age

• administration of doxycycline at 4 months of age after the establishment of clinical disease for 5 months, fails to reverse the disease

homeostasis/metabolism

abnormal circulating enzyme level ( J:205907 )

♀ • females in which doxycycline is removed at 4 weeks of age show an increase in serum levels of glutamic-oxaloacetic transaminase, indicating muscle parenchymal damage

increased circulating creatine kinase level ( J:205907 )

♀ • females in which doxycycline is removed at 4 weeks of age show an increase in serum levels of creatine kinase, indicating muscle parenchymal damage

abnormal cytokine level ( J:205907 )

♀ • MIP1-alpha, MCP-1, and IL-15 are increased in muscle tissues of females in which doxycycline is removed at 4 weeks of age

skeleton

abnormal spine curvature ( J:205907 )

♀ • females in which doxycycline is removed at 4 weeks of age, show arched spine by 5-7 months of age

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
myositis		DOID:633	OMIM:160750	J:205907