Analysis Tools
mortality/aging
|
• reduced lifespan, with an average half-life of 36 weeks
|
|
• perinatal lethality in some mutants, probably due to heart insufficiency and hematopoietic defects
• pregnant females treated with the MEK inhibitor PD0325901 from E7.5 to P9 and then direct treatment of mutant pups until P21 completely rescues perinatal lethality and heart defects observed in P0 pups, as well as the craniofacial dysmorphia and growth defects, however beginning MEK inhibitor treatment at P21 does not ameliorate the developmental defects
• median survival of mutants treated with the MEK inhibitor PD0325901 is 30% longer than vehicle treated mutants
|
growth/size/body
|
• cardiac hyperplasia is already evident at E13.5
• increase in heart/body weight ratio characterizes the cardiac hyperplasia at 4 months of age
|
|
• facial dysmorphia
|
|
• pronounced triangular facial appearance with a shorter distance between the ears and the nose, blunter snout, and wider separation between the eyes
|
|
• blunter snout
|
|
• shorter distance between the ears and the nose
|
|
• surviving mice are smaller at weaning but have normal weight at birth
|
|
• surviving mice are smaller at weaning but have normal weight at birth
• at 4 weeks of age, males weigh only 72% of wild-type mice, however this difference is ameliorated by 3 months of age
|
|
• at 4 weeks of age, males are 23% shorter than wild-type mice, however this difference is ameliorated by 3 months of age
|
|
• severe splenomegaly at 4 months of age
|
craniofacial
|
• increase in skull width and height along with reduction in length results in a rounder skull with bigger volume
|
|
• at 4 months of age
|
|
• at 4 months of age
|
|
• at 4 months of age
|
|
• facial dysmorphia
|
|
• pronounced triangular facial appearance with a shorter distance between the ears and the nose, blunter snout, and wider separation between the eyes
|
|
• blunter snout
|
|
• shorter distance between the ears and the nose
|
hearing/vestibular/ear
|
• shorter distance between the ears and the nose
|
hematopoietic system
|
• mice develop a myeloproliferative disorder and exhibit lymphoid and myeloid infiltrates in a variety of organs, including liver, kidney, and lung
• treatment with the MEK inhibitor PD0325901 slows down progression but does not prevent myeloproliferative disease
|
|
• splenomegaly is due to congestion and increased extramedullary hematopoiesis
|
|
• severe splenomegaly at 4 months of age
|
|
• increase in numbers of common myeloid progenitors (Lin-/IL7Ralpha-/Sca-1-/c-Kit+/FcgammaRlow/CD34+)
|
|
• splenomegaly is due to congestion and increased extramedullary hematopoiesis
|
|
• increase in numbers of granulocyte-macrophage progenitors (Lin-/IL7Ralpha-/Sca-1-/c-Kit+/FcgammaRhigh/CD34+)
• however, numbers of megakaryocyte-erythroid progenitors seem normal
|
|
• slight increase in numbers of common lymphoid progenitors (Lin-/IL7Ralpha+/Sca-1low/c-Kitlow)
|
|
• decrease in the percentage of CD8+ T cells
|
|
• increase in the number of leukocytes in peripheral blood , mainly due to expansion of neutrophils, eosinophils, and basophils
|
|
• expansion of myeloid cells in the spleen, with increased levels of both Gr1+/CD11b+ and CD11b+ cells
|
|
• mice exhibit an increase in LSK (Lin-/Sca-1+/c-Kit+) cells in the bone marrow
|
|
• bone marrow cells proliferate in the absence of cytokines unlike wild-type cells and proliferate more robustly than control bone marrow cells in the presence of cytokines
|
cardiovascular system
|
• splenomegaly is due to congestion and increased extramedullary hematopoiesis
|
|
• thickening of all chambers
• expansion of Sca-1+/PDGFRalpha+/CD31- cardiac stem cells from hearts of unweaned (P10-P14) mice
• however, mice do not display hypertension, heart fibrosis or cardiovascular remodeling
|
|
• increased size of heart is due to an increase in numbers of cardiomyocytes and not by increased cell size
|
|
• cardiac hyperplasia is already evident at E13.5
• increase in heart/body weight ratio characterizes the cardiac hyperplasia at 4 months of age
|
|
• cardiac output is increased in 4 month old mice
|
|
• fractional shortening is increased in 4 month old mice
• 4 month old mice show increased wall thickness in systole, systolic wall thickening, and left ventricle mass, and increased end diastolic volume, however end systolic volume is normal and no differences in the wall thickness in diastole, ejection fraction, or heart rate indicating normal heart function
|
|
• higher proliferation rate in cardiomyocytes of 4 month old mice
|
cellular
|
• mice that die at P0 show focal necrosis in tissues ilike the liver and muscle
|
|
• MEFs show higher growth rate than wild-type MEFs when grown in culture
|
immune system
|
• splenomegaly is due to congestion and increased extramedullary hematopoiesis
|
|
• severe splenomegaly at 4 months of age
|
|
• decrease in the percentage of CD8+ T cells
|
|
• increase in the number of leukocytes in peripheral blood , mainly due to expansion of neutrophils, eosinophils, and basophils
|
muscle
|
• increased size of heart is due to an increase in numbers of cardiomyocytes and not by increased cell size
|
|
• fractional shortening is increased in 4 month old mice
• 4 month old mice show increased wall thickness in systole, systolic wall thickening, and left ventricle mass, and increased end diastolic volume, however end systolic volume is normal and no differences in the wall thickness in diastole, ejection fraction, or heart rate indicating normal heart function
|
renal/urinary system
|
• kidneys frequently show infiltration from hematopoietic cells
• however, no abnormalities are seen in renal morphology or histology
|
skeleton
|
• increase in skull width and height along with reduction in length results in a rounder skull with bigger volume
|
|
• at 4 months of age
|
|
• at 4 months of age
|
|
• at 4 months of age
|
vision/eye
|
• wider separation between the eyes
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Noonan syndrome 3 | DOID:0060581 |
OMIM:609942 |
J:223433 | |
