Thrombophilia in mice expressing a tissue factor variant lacking its transmembrane and cytosolic domain.
Mice with a targeted truncation in the gene encoding tissue factor of blood coagulation (TF) to eliminate the cytosolic domain and carrying a neo(R) cassette in intron 5 unexpectedly displayed severe spontaneous thrombosis in various vascular beds. Thrombosis was observed in heterozygous TF(+/neo) mice, causing death of over 50% of adults within 36 weeks of birth, and fulminantly exacerbating in pregnant females. Homozygous TF(neo/neo) mice were more severely affected and died within 7 weeks after birth. These TF(neo) mice primarily synthesized a mutant mRNA aberrantly spliced from exon 5 to neo(R), encoding an apparently non-vesicle-binding soluble TF lacking both the transmembrane and cytosolic domain, but still capable of blood coagulation induction. This severe thrombotic phenotype associated with the presence of a non-anchored soluble TF variant underscores the recently recognized significance of circulating TF for thrombus formation and development.
Melis
Els
E
The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology (VIB), KULeuven Campus Gasthuisberg, Leuven B-3000, Belgium.
Moons
Lieve
L
Arnout
Jef
J
Hoylaerts
Marc F
MF
Collen
Désiré
D
Carmeliet
Peter
P
Dewerchin
Mieke
M
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed / Q000235:genetics; D010641:Phenotype; D017434:Protein Structure, Tertiary; D015996:Survival Rate; D019851:Thrombophilia / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D013925:Thromboplastin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
D013925:Thromboplastin