A viable mouse model of factor X deficiency provides evidence for maternal transfer of factor X.
Activated factor X (FXa) is a vitamin K-dependent serine protease that plays a pivotal role in blood coagulation by converting prothrombin to thrombin. There are no reports of humans with complete deficiency of FX, and knockout of murine F10 is embryonic or perinatal lethal.



We sought to generate a viable mouse model of FX deficiency.



We used a socket-targeting construct to generate F10-knockout mice by eliminating F10 exon 8 (knockout allele termed F10(tm1Ccmt), abbreviated as '-'; wild-type '+'), and a plug-targeting construct to generate mice expressing a FX variant with normal antigen levels but low levels of FX activity [4-9% normal in humans carrying the defect, Pro343-->Ser, termed FX Friuli (mutant allele termed F10(tm2Ccmt), abbreviated as F)].



F10 knockout mice exhibited embryonic or perinatal lethality. In contrast, homozygous Friuli mice [F10 (F/F)] had FX activity levels of approximately 5.5% (sufficient to rescue both embryonic and perinatal lethality), but developed age-dependent iron deposition and cardiac fibrosis. Interestingly, F10 (-/F) mice with FX activity levels of 1-3% also showed complete rescue of lethality. Further study of this model provides evidence supporting a role of maternal FX transfer in the embryonic survival.



We demonstrate that, while complete absence of FX is incompatible with murine survival, minimal FX activity as low as 1-3% is sufficient to rescue the lethal phenotype. This viable low-FX mouse model will facilitate the development of FX-directed therapies as well as investigation of the FX role in embryonic development.
Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
S J
SJ
Tai
R W
RW
Herzog
P
P
Margaritis
V R
VR
Arruda
K
K
Chu
J A
JA
Golden
P A
PA
Labosky
K A
KA
High
D019943:Amino Acid Substitution; D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology; D005091:Exons / Q000235:genetics; D005170:Factor X / Q000235:genetics*; D005171:Factor X Deficiency / Q000150:complications / Q000235:genetics*; D005260:Female; D005313:Fetal Death / Q000235:genetics; D005355:Fibrosis; D018390:Gene Targeting / Q000379:methods; D005804:Genes, Lethal; D005816:Genetic Complementation Test; D018392:Genomic Imprinting / Q000235:genetics*; D005838:Genotype; D006486:Hemosiderosis / Q000209:etiology; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic / Q000097:blood / Q000235:genetics*; D023421:Models, Animal; D009206:Myocardium / Q000473:pathology
C071676:factor X Friuli; D005170:Factor X