Phenotypes associated with this allele

• Allele Symbol: Proc^tm1Fjc
• Allele Name: targeted mutation 1, Francis J Castellino
• Allele ID: MGI:2183063
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Proc^tm1Fjc/Proc^tm1Fjc	involves: 129S1/Sv * 129X1/SvJ * Swiss	MGI:2669271
cx2	F11^tm1Gjb/F11^tm1Gjb Proc^tm1Fjc/Proc^tm1Fjc	involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:3665568
cx3	F7^tm1Pec/F7^tm1Pec Proc^tm1Fjc/Proc^tm1Fjc	involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:4839937
cx4	F7^tm1Pec/F7^+ Proc^tm1Fjc/Proc^tm1Fjc	involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:4839992

Genotype
MGI:2669271

hm1

• Allelic Composition: Proc^tm1Fjc/Proc^tm1Fjc
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * Swiss

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

mortality/aging

perinatal lethality, complete penetrance ( J:50527 )

• most homozygotes (8 of 12) are stillborn in the absence of macroscopic abnormalities

• the rest are severely bruised in the head and die within a few hours of birth

neonatal lethality, complete penetrance ( J:50527 )

• homozygotes delivered by Cesarean section are macroscopically normal but die within 24 hrs of birth

homeostasis/metabolism

abnormal blood coagulation ( J:50527 )

• homozygotes display severe perinatal consumptive coagulopathy in the brain and liver

abnormal brain thrombosis ( J:50527 )

• at E17.5, mutant embryos show normal organ and blood vessel development, but exhibit scattered microvascular thrombosis in the telencephalic region of the brain; early signs of thrombosis are first evident at E12.5 and progress thereafter

• at E17.5 or later, hemostatic brain abnormalities are variable and range from minimal clotting and no bleeding to widespread fibrin deposition in the brain with severe bleeding events in the forebrain near the lateral ventricles

abnormal cardiac thrombosis ( J:50527 )

• late stage embryos (>E17.5) and newborn homozygotes display occasional clotting in the heart

abnormal lung thrombosis ( J:50527 )

• late stage embryos (>E17.5) and newborn homozygotes display occasional clotting in the lungs

liver/biliary system

liver inflammation ( J:50527 )

• in severe cases, infiltrating leukocytes are observed in the liver interstitia

focal hepatic necrosis ( J:50527 )

• at E17.5, mutant embryos display focal necrosis in the liver

• newborn homozygotes exhibit advanced hepatic tissue necrosis with depletion of red blood cells and increased levels of fibrin(ogen) deposition

liver degeneration ( J:50527 )

• in severe cases, loss of hepatocytes and deterioration of the extracellular matrix are observed

liver fibrosis ( J:50527 )

• at E17.5, most mutant embryos display increased interstitial fibrin in all liver lobes

• fibrin deposition in the liver is first evident but minimal at E12.5 and progresses thereafter

cardiovascular system

bruising ( J:50527 )

• 4 of 12 homozygotes born naturally exhibit severe bruising in the head region (subdural space and brain)

intracranial hemorrhage ( J:50527 )

• newborn homozygotes exhibit extensive brain necrosis with secondary edema and severe bleeding near the brain lateral ventricles, close to sites of fibrin deposition; as a result, intracranial pressures are increased

• dural vessels are significantly dilated but show no signs of bleeding

behavior/neurological

abnormal suckling behavior ( J:50527 )

• homozygotes delivered by Cesarean section are cared for by the foster mother but fail to nurse

immune system

liver inflammation ( J:50527 )

• in severe cases, infiltrating leukocytes are observed in the liver interstitia

abnormal innate immunity ( J:50527 )

• at E17.5, most mutant embryos display increased interstitial fibrin(ogen) deposition in the liver, which becomes pronounced at birth; fibrin deposition in the liver is first evident but minimal at E12.5

• newborn homozygotes exhibit notable fibrin(ogen) deposition in the brain microvasculature; a small degree of fibrin deposition is first noted in the telencephalon at E12.5-E14.5 near sites of thrombosis

• traces of fibrin deposition are also observed in the glomeruli and tubuli of neonatal kidneys

• homozygotes show absence of plasma clottable fibrinogen both at E17.5 and neonatally, indicating fibrinogen depletion due to consumptive coagulopathy

nervous system

intracranial hemorrhage ( J:50527 )

• newborn homozygotes exhibit extensive brain necrosis with secondary edema and severe bleeding near the brain lateral ventricles, close to sites of fibrin deposition; as a result, intracranial pressures are increased

• dural vessels are significantly dilated but show no signs of bleeding

Genotype
MGI:3665568

cx2

• Allelic Composition: F11^tm1Gjb/F11^tm1Gjb; Proc^tm1Fjc/Proc^tm1Fjc
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6

mortality/aging

premature death ( J:67398 )

• animals surviving neonatal period either died or were euthanized between 13 and 94 days of age

• oldest survivor euthanized at 94 days of age with severe inflammation, edema, and gangrene in extremities

neonatal lethality, incomplete penetrance ( J:67398 )

• only 8 double homozygotes survived neonatal lethality due to coagulopathy typical of Proc^tm1Fjc homozygosity

behavior/neurological

decreased locomotor activity ( J:67398 )

• sedentary

growth/size/body

enlarged heart ( J:67398 )

postnatal growth retardation ( J:67398 )

• severe

respiratory system

abnormal respiratory system morphology ( J:67398 )

abnormal pulmonary alveolus morphology ( J:67398 )

• consolidation

• hemorrhage

• fibroblast infiltration of alveolar space

thick pulmonary interalveolar septum ( J:67398 )

abnormal trachea morphology ( J:67398 )

• degeneration of peritracheal muscle and fat

abnormal respiratory system physiology ( J:67398 )

lung hemorrhage ( J:67398 )

• hemorrhagic lesions

lung inflammation ( J:67398 )

• acute and chronic inflammation

• perivascular lymph vessels are distended

respiratory distress ( J:67398 )

cardiovascular system

increased vascular endothelial cell number ( J:67398 )

• arterial neointimal formation

abnormal heart morphology ( J:67398 )

myocardial fiber degeneration ( J:67398 )

• myocardial degeneration

myocardium necrosis ( J:67398 )

• multifocal vacuolization and necrosis

enlarged heart ( J:67398 )

cardiac fibrosis ( J:67398 )

• in atria

abnormal cardiovascular system physiology ( J:67398 )

• ventricular infarction

• atrial clotting

abnormal lymph circulation ( J:67398 )

• significant amounts of lymphatic fluid sometimes accumulate in the thorax

internal hemorrhage ( J:67398 )

• in various internal organs and leg muscles

• in bladder at E17.5

lung hemorrhage ( J:67398 )

• hemorrhagic lesions

intracranial hemorrhage ( J:67398 )

• in the brain and skull plate

• hemorrhage beneath the skull plate seen at E17.5

liver hemorrhage ( J:67398 )

• hemorrhagic cysts often seen at the edges of the liver

lymph node hemorrhage ( J:67398 )

• enlarged lymph nodes with areas of hemorrhage

immune system

abnormal lymph circulation ( J:67398 )

• significant amounts of lymphatic fluid sometimes accumulate in the thorax

lymph node hemorrhage ( J:67398 )

• enlarged lymph nodes with areas of hemorrhage

abnormal neutrophil morphology ( J:67398 )

• hypersegmentation

decreased neutrophil cell number ( J:67398 )

decreased leukocyte cell number ( J:67398 )

abnormal lymph node morphology ( J:67398 )

abnormal lymph node cortex morphology ( J:67398 )

• areas of atrophy and edema

enlarged lymph nodes ( J:67398 )

• with areas of hemorrhage

lung inflammation ( J:67398 )

• acute and chronic inflammation

• perivascular lymph vessels are distended

hematopoietic system

anisocytosis ( J:67398 )

increased number of Howell-Jolly bodies ( J:67398 )

• Howell-Jolly bodies sometimes seen

abnormal neutrophil morphology ( J:67398 )

• hypersegmentation

decreased neutrophil cell number ( J:67398 )

decreased leukocyte cell number ( J:67398 )

reticulocytosis ( J:67398 )

homeostasis/metabolism

abnormal thrombosis ( J:67398 )

• near truncus pulmonalis

• occasionally see significant thrombi in the larger blood vessels

• intravascular thrombosis in liver

liver/biliary system

liver hemorrhage ( J:67398 )

• hemorrhagic cysts often seen at the edges of the liver

abnormal liver morphology ( J:67398 )

• areas of hyperplasia, mineralization and hemorrhage

hepatic necrosis ( J:67398 )

• seen to varying degrees at E17.5

liver fibrosis ( J:67398 )

• fibrotic tissue often seen on edges of the liver

nervous system

intracranial hemorrhage ( J:67398 )

• in the brain and skull plate

• hemorrhage beneath the skull plate seen at E17.5

muscle

myocardial fiber degeneration ( J:67398 )

• myocardial degeneration

myocardium necrosis ( J:67398 )

• multifocal vacuolization and necrosis

cellular

gangrene ( J:67398 )

• gangrene seen in the extremities (nose, tail and paws) of oldest survivor euthanized at 94 days of age with severe inflammation and edema

Genotype
MGI:4839937

cx3

• Allelic Composition: F7^tm1Pec/F7^tm1Pec; Proc^tm1Fjc/Proc^tm1Fjc
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6

Hemorrhage and edema in F7^tm1Pec/F7^tm1Pec Proc^tm1Fjc/Proc^tm1Fjc mice

mortality/aging

neonatal lethality, complete penetrance ( J:61481 )

• genotyping analysis indicated that, at E17.5 dpc, double homozygous mutant embryos were present at the expected Mendelian frequency; however, double homozygous mutant neonates died immediately after birth

cardiovascular system

abnormal dorsal aorta morphology ( J:61481 )

• fibrin deposition is observed at E12.5

hemorrhage ( J:61481 )

• all E14.5 dpc double mutant embryos displayed extensive peripheral and internal bleeding and fibrin deposition, with concomitant anemia

• at E14.5 and E17.5, yolk sac development and blood flow generally appeared normal; however, one out of five embryos studied showed blood pools within the amniotic sac

• at E14.5, fibrin deposition, hemorrhage, and tissue degradation was observed in the brain, along the spine, and in the liver; blood could not be collected by intracardiac puncture due to massive hemorrhaging

• at E17.5 dpc, four of five embryos were alive, but displayed severe edema, anemia, subcutaneous bleeding at the joints, and peripheral bleeding, as well as necrosis around the nasal area; no hemorrhage was observed in the mutant placenta

• at E17.5, fibrotic patches were observed in the liver, and variable bleeding and necrosis was found in the brain; in one case, bleeding was also evident in the stomach and intestinal tract

• at E17.5, the ventricles were anemic, and the atria were clotted displaying abnormal collagen invasion in the internal atrial tissue

• at E17.5, interstitial fibrin deposition was also seen in areas surrounding fibrotic lesions

• In contrast to the E14.5 dpc and E17.5 dpc time points, E12.5 dpc double homozygous mutant embryos appeared developmentally normal, with no obvious external bleeding anomalies; however, fibrin deposition, in the absence of hemorrhage, was noted in the liver interstitia and in vessels in the brain, neural canal, caudal artery, pulmonary cavity, dorsal aorta, and left hind-limb bud

• areas of intra- and extravascular fibrin deposition did not stain positively for P-selectin-positive activated platelets

homeostasis/metabolism

abnormal blood coagulation ( J:61481 )

• double homozygous mutant embryos exhibited an intra- and extravascular progressive coagulopathy as early as E14.5 dpc

hydrops fetalis ( J:61481 )

• peripheral edema by E17.5

Genotype
MGI:4839992

cx4

• Allelic Composition: F7^tm1Pec/F7⁺; Proc^tm1Fjc/Proc^tm1Fjc
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6

mortality/aging

neonatal lethality, complete penetrance ( J:61481 )

• compound mutant embryos were present at their expected Mendelian frequency

• compound mutant mice were born but succumbed to consumptive coagulopathy

• postnatal underrepresentation was due to the inability to identify these neonates before their death and consumption by their parents

cardiovascular system

internal hemorrhage ( J:61481 )

• the liver, brain, and atria of these compound mutant mice showed a similar hemorrhage, fibrin deposition, and inflammatory cell infiltration as double homozygous mutant embryos; however no severe edema or peripheral bleeding were observed

• at E14.5 dpc, 2 out of 7 compound mutant mice displayed variable bleeding spots on the skin and blood pools within the amniotic sac; interstitial fibrin deposition was detected in the liver, and to a lesser extent in the brain, in the absence of peripheral hemorrhage

homeostasis/metabolism

abnormal blood coagulation ( J:61481 )

• compound mutant embryos displayed an organ coagulopathy similar to that observed in double homozygous mutant embryos