Analysis Tools
mortality/aging
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• homozygotes surviving the first postnatal week are indistinguishable from wild-type littermates
• however, adult homozygotes show an increased frequency of sudden death upon stress, such as induction of anesthesia
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cardiovascular system
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• at 40 weeks, mutant hearts exhibit dilated and deformed capillaries, with an enlarged space between cardiomyocytes and adjacent capillary vessels
• in contrast, the structure of larger (coronary) vessels appears unaffected, as shown by microfil perfusion experiments
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• at 40 weeks of age in the heart
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• at 40 weeks, homozygotes show a significant increase in cardiomyocyte size as well as widening of the extracellular matrix space and multiple foci of cardiomyocyte degeneration, with no changes in integrin beta1D content, DGC components or sarcolemma integrity
• as early as 4-8 weeks, mutant cardiomyocytes show an uneven border and an increased distance between myocytes and adjacent capillary vessels
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• at 40 weeks, homozygotes show a significant increase in cardiomyocyte size
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• at 40 weeks, homozygotes show multiple foci of cardiomyocyte degeneration
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• at autopsy, homozygotes dying suddenly upon exposure to anesthesia display enlarged hearts
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• adult homozygotes exhibit progressive cardiac hypertrophy: by 40 weeks, their heart weight/body weight ratio is significantly higher relative to wild-type mice (6.25 0.22 vs 5.03 0.40, respectively), despite a normal body weight
• no differences in heart or body weight are noted at 16 weeks of age
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• at 36-40 weeks, homozygotes exhibit a significant increase in LV mass
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• at 36-40 weeks, homozygotes show a dilated LV end diastolic and systolic diameter, with variable severity among individual mice
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• at 40 weeks, mutant hearts display wide intercellular space and interstitial and perivascular fibrosis
• ultrastructurally, intercellular space is enlarged as early as 4-8 weeks
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• at 16-20 weeks, mutant hearts exhibit upregulation of hypoxia-induced genes, suggesting sustained cardiac ischemia associated with cardiomyocyte degeneration and fibrosis
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hemorrhage
(
J:98348
)
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• homozygotes display hemorrhages at birth but mature normally and are fertile as adults
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• adult homozygotes exhibit defective microvascular circulation
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• at 40 weeks, homozygotes show a reduction in LV % fractional shortening relative to wild-type mice, indicating cardiac dysfunction
• however, cardiomyocytes isolated from 16-20-week-old homozygotes display improved contractility in vitro (i.e. increased maximum rates of contraction and relaxation), suggesting a compensatory response of hypertrophic myocytes to chronic cell loss from hypoxia/ischemia
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• during echocardiography, 50% of 40-week-old homozygotes display intermittent sinus arrhythmia
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• during echocardiography, 50% of 40-week-old homozygotes display intermittent bradycardia
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• at 40 weeks, mutant hearts show multiple foci of muscle degeneration in both RV and LV walls, interventricular septum, right and left atria, and near the atrial ventricular node, with variable severity among individual mice
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homeostasis/metabolism
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• at 16-20 weeks, mutant hearts exhibit upregulation of hypoxia-induced genes, indicating a sustained state of cardiac hypoxia
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muscle
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• at 40 weeks, homozygotes show a significant increase in cardiomyocyte size as well as widening of the extracellular matrix space and multiple foci of cardiomyocyte degeneration, with no changes in integrin beta1D content, DGC components or sarcolemma integrity
• as early as 4-8 weeks, mutant cardiomyocytes show an uneven border and an increased distance between myocytes and adjacent capillary vessels
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• at 40 weeks, homozygotes show a significant increase in cardiomyocyte size
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• at 40 weeks, homozygotes show multiple foci of cardiomyocyte degeneration
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• at 36-40 weeks, homozygotes exhibit a significant increase in LV mass
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• at 40 weeks, homozygotes show a reduction in LV % fractional shortening relative to wild-type mice, indicating cardiac dysfunction
• however, cardiomyocytes isolated from 16-20-week-old homozygotes display improved contractility in vitro (i.e. increased maximum rates of contraction and relaxation), suggesting a compensatory response of hypertrophic myocytes to chronic cell loss from hypoxia/ischemia
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• at 40 weeks, mutant hearts show multiple foci of muscle degeneration in both RV and LV walls, interventricular septum, right and left atria, and near the atrial ventricular node, with variable severity among individual mice
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behavior/neurological
limb grasping
(
J:98086
)
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• when suspended by their tail, mice exhibit retraction of hindlimbs towards body with toes clenched that progress to rigid rearward extension unlike in wild-type mice
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• homozygotes show a greater variation in step length, measured as the difference between the longest and shortest step, suggesting ataxia
• when held by the tail, mutants tend to extend their legs backward with the paws turned upside down in a spastic-like manner
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• all homozygotes show frequent arrests in swimming, some lasting >5 sec, with mice just floating on the surface or swimming in a severely uncoordinated manner
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nervous system
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• the number of Schwann cells in adult mice is decreased
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• at P6, mutant sciatic nerves have thinner myelin sheaths with several dysmyelinated areas where unmyelinated axons of all calibers are grouped in bundles, in an unsorted manner
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• at P6, most large-caliber axons in the sciatic nerve have thinner myelin sheaths; in some areas, they are totally without myelin
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• at P6, mutant sciatic nerves display axon bundles that are not invested by Schwann cells and have generally thin myelin sheaths
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• mice exhibit amyelinated axons of peripheral nerves and occasionally roots
(J:98086)
• however, mice exhibit normal basal lamina on Schwann cells
(J:98086)
• neonatal homozygotes develop a dysmyelinating neuropathy, not observed at P0
(J:98348)
• at P6, mutant sciatic nerves have thinner myelin sheaths with several dysmyelinated areas where unmyelinated axons of all calibers are grouped in bundles, in an unsorted manner
(J:98348)
• such bundles are poorly or not at all invested by Schwann cell cytoplasm
(J:98348)
• in a few cases, axons are seen without myelin, Schwann cell cytoplasm, or even basal lamina
(J:98348)
• in addition, several myelinated and unmyelinated axons may be surrounded by a common myelin sheath
(J:98348)
• similar pathology is also observed in ventral and dorsal roots
(J:98348)
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growth/size/body
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• at autopsy, homozygotes dying suddenly upon exposure to anesthesia display enlarged hearts
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• adult homozygotes exhibit progressive cardiac hypertrophy: by 40 weeks, their heart weight/body weight ratio is significantly higher relative to wild-type mice (6.25 0.22 vs 5.03 0.40, respectively), despite a normal body weight
• no differences in heart or body weight are noted at 16 weeks of age
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• at 36-40 weeks, homozygotes exhibit a significant increase in LV mass
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cellular
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• at 40 weeks, mutant hearts display wide intercellular space and interstitial and perivascular fibrosis
• ultrastructurally, intercellular space is enlarged as early as 4-8 weeks
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