In utero transplantation of wild-type fetal liver cells rescues factor X-deficient mice from fatal neonatal bleeding diatheses

Rosen, Elliot D.; Cornelissen, Ivo; Zhong, Liang; Zollman, Amy; Casad, Michelle; Roahrig, Julie; Suckow, Mark A.; Castellino, F.J.

doi:10.1046/j.1538-7836.2003.00030.x

Cited by 19 publications

(14 citation statements)

References 38 publications

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“…These data in humans are consistent with the data presented here; mice with homozygous deletion of the F10 gene show a reduction in numbers occurring as early as E11.5 and are thus born in reduced numbers (approximately 50% of expected numbers), exhibiting 100% perinatal mortality. Because of an interest in developing new approaches for the treatment of bleeding disorders [13][14][15][16], and to analyze the potential role of FX in pathophysiological processes such as sepsis and metastasis [17,18], we wished to develop a viable murine model of severe FX deficiency. The only extant model [15] requires in utero transplantation of wild-type fetal liver, a cumbersome manipulation and not transmissible from one generation to the next.…”

Section: Discussionmentioning

confidence: 99%

A viable mouse model of factor X deficiency provides evidence for maternal transfer of factor X

Tai¹,

Herzog²,

Margaritis³

et al. 2008

Journal of Thrombosis and Haemostasis

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Background: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. Objective:We sought to generate a viable mouse model of FX deficiency. Methods:We used a socket-targeting construct to generate F10-knockout mice by eliminating F10 exon 8 (knockout allele termed F10tm1Ccmt, 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 F10tm2Ccmt, abbreviated as F)]. Results:F10 knockout mice exhibited embryonic or perinatal lethality. In contrast, homozygous Friuli mice [F10 (F/F)] had FX activity levels of ∼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. Conclusions: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.

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Section: Discussionmentioning

confidence: 99%

A viable mouse model of factor X deficiency provides evidence for maternal transfer of factor X

Tai¹,

Herzog²,

Margaritis³

et al. 2008

Journal of Thrombosis and Haemostasis

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show abstract

“…The only extant model [15] requires in utero transplantation of wild-type fetal liver, a cumbersome manipulation and not transmissible from one generation to the next. The plug-and-socket methodology utilized here facilitates repeated modification of a specific locus as well as expression of the gene of interest under the control of the endogenous promoter, thus preserving the temporal and spatial patterns of expression during embryonic development.…”

Section: Discussionmentioning

confidence: 99%

A viable mouse model of factor X deficiency provides evidence for maternal transfer of factor X

Tai¹,

Herzog²,

Margaritis³

et al. 2008

J Thromb Haemost

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. A viable mouse model of factor X deficiency provides evidence for maternal transfer of factor X. J Thromb Haemost 2008; 6: 339-45.Summary. Background: 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. Objective: We sought to generate a viable mouse model of FX deficiency. Methods: We used a socket-targeting construct to generate F10-knockout mice by eliminating F10 exon 8 (knockout allele termed F10 tm1Ccmt , abbreviated as Ô)Õ; wildtype Ô+Õ), 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, Pro 343 fi Ser, termed FX Friuli (mutant allele termed F10 tm2Ccmt , abbreviated as F)]. Results: F10 knockout mice exhibited embryonic or perinatal lethality. In contrast, homozygous Friuli mice [F10 (F/F)] had FX activity levels of 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. Conclusions: 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.

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“…[39][40][41][42][43][44][45][46][47][48][49][50] Patients with afibrinogenemia, or severe FII, FVII, and FX deficiencies, show similar bleeding manifestations and usually require regular replacement therapy. Lman1 gene knockout mice duplicate the FV1FVIII-deficient phenotype in humans, albeit with a milder presentation, due to a lesser reduction in plasma FV and FVIII.…”

Section: Mutational Spectrum Of Rare Bleeding Disordersmentioning

confidence: 99%

Genetic sequence analysis of inherited bleeding diseases

Peyvandi

Kunicki

Lillicrap

2013

Blood

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The genes encoding the coagulation factor proteins were among the first human genes to be characterized over 25 years ago. Since then, significant progress has been made in the translational application of this information for the 2 commonest severe inherited bleeding disorders, hemophilia A and B. For these X-linked disorders, genetic characterization of the disease-causing mutations is now incorporated into the standard of care and genetic information is used for risk stratification of treatment complications. With electronic databases detailing >2100 unique mutations for hemophilia A and >1100 mutations for hemophilia B, these diseases are among the most extensively characterized inherited diseases in humans. Experience with the genetics of the rare bleeding disorders is, as expected, less well advanced. However, here again, electronic mutation databases have been developed and provide excellent guidance for the application of genetic analysis as a confirmatory approach to diagnosis. Most recently, progress has also been made in identifying the mutant loci in a variety of inherited platelet disorders, and these findings are beginning to be applied to the genetic diagnosis of these conditions. Investigation of patients with bleeding phenotypes without a diagnosis, using genome-wide strategies, may identify novel genes not previously recognized as playing a role in hemostasis.

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In utero transplantation of wild-type fetal liver cells rescues factor X-deficient mice from fatal neonatal bleeding diatheses

Cited by 19 publications

References 38 publications

A viable mouse model of factor X deficiency provides evidence for maternal transfer of factor X

A viable mouse model of factor X deficiency provides evidence for maternal transfer of factor X

A viable mouse model of factor X deficiency provides evidence for maternal transfer of factor X

Genetic sequence analysis of inherited bleeding diseases

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