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

Tai, Shing Jen; Herzog, Roland W.; Margaritis, Paris; Arruda, Valder R.; Chu, Kirk; Golden, Jeffrey A.; Labosky, Patricia A.; High, Katherine A.

doi:10.1111/j.1538-7836.2007.02849.x

Cited by 30 publications

(9 citation statements)

References 18 publications

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“…FX knockout mice show embryonic or perinatal lethality and this is consistent with the hypothesis that a complete absence of FX is a lethal disorder [20]. However, mice with FX activity levels of 1-3% of normal show a complete rescue of lethality [21]. The earliest reported molecular abnormality affecting the F10 gene was reported by Scambler and Williamson who described a female monosomic for 13q34 and who was found to be deficient in FVII and FX [4].…”

Section: Molecular Basis Of Factor X Deficiencysupporting

confidence: 80%

Factor X and Factor X Deficiency

Perry

2014

Textbook of Hemophilia

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Section: Molecular Basis Of Factor X Deficiencysupporting

confidence: 80%

Factor X and Factor X Deficiency

Perry

2014

Textbook of Hemophilia

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“…To model the F10 rs3211783 variant and FX deficiency in general, mice with the Friuli allele of F10 (referred to as F10 F/F throughout), which have reduced FX activity, were used. As deletion of F10 is an embryonic lethal mutation, this is the only known murine model of FX deficiency (28). We hypothesized that FX deficiency would cause an increase in bacterial replication over the course of infection, as humans with an FX mutation have increased rates of clinically coded bacterial infection.…”

Section: Resultsmentioning

confidence: 99%

A Phenome-Wide Association Study Uncovers a Pathological Role of Coagulation Factor X duringAcinetobacter baumanniiInfection

et al. 2019

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Coagulation and inflammation are interconnected, suggesting that coagulation plays a key role in the inflammatory response to pathogens. A phenome-wide association study (PheWAS) was used to identify clinical phenotypes of patients with a polymorphism in coagulation factor X. Patients with this single nucleotide polymorphism (SNP) were more likely to be hospitalized with hemostatic and infection-related disorders, suggesting that factor X contributes to the immune response to infection. To investigate this, we modeled infections by human pathogens in a mouse model of factor X deficiency. Factor X-deficient mice were protected from systemicAcinetobacter baumanniiinfection, suggesting that factor X plays a role in the immune response toA. baumannii. Factor X deficiency was associated with reduced cytokine and chemokine production and alterations in immune cell population during infection: factor X-deficient mice demonstrated increased abundance of neutrophils, macrophages, and effector T cells. Together, these results suggest that factor X activity is associated with an inefficient immune response and contributes to the pathology ofA. baumanniiinfection.

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“…In spite of the life‐threatening symptoms requiring continuous prophylaxis, the trace FX function would prevent a lethal phenotype, thus permitting perinatal survival. In addition, we are also aware that the possibility of maternal transfer of small amounts of functional FX could have further contributed to embryonic survival.…”

Section: Discussionmentioning

confidence: 99%

Missense changes in the catalytic domain of coagulation factor X account for minimal function preventing a perinatal lethal condition

et al. 2019

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Introduction Inherited deficiencies in the coagulation pathway provide diversified models to investigate the molecular bases of perinatal lethality associated with null‐like variants. Differently from X‐linked haemophilias, homozygous/doubly heterozygous null variants in the rare autosomally inherited deficiency of factor X (FX) might be incompatible with perinatal survival. Aim To provide experimental evidence about the null/close‐to‐null FX function. Methods The residual secreted (ELISA) and functional (thrombin generation assays) protein levels associated with the novel nonsense (c.1382G>A; p.Trp461Ter) and missense (c.752T>C; p.Leu251Pro) variants, found in the proposita with life‐threatening symptoms at birth, were characterized through recombinant (r)FX expression. Results The rFX‐461Ter showed very low secretion and undetectable function. Expression and function of the predicted readthrough‐deriving missense variants (rFX‐461Tyr, rFX‐461Gln) were also severely impaired. These unfavourable features, due to nucleotide and protein sequence constraints, precluded functional readthrough over the 461 stop codon. Differently, the poorly secreted rFX‐251Pro variant displayed residual function that was characterized by anti‐TFPI aptamer‐based amplification or selective inhibition of activated FX function by fondaparinux in plasma and found to be reduced by approximately three orders of magnitude. Similarly to the rFX‐251Pro, a group of catalytic domain missense variants cause poorly secreted molecules with modest function in FX‐deficient patients with life‐threatening symptoms. Conclusions Our data, contributing to the knowledge of the very severe FX deficiency forms, support life‐saving requirement of trace FX function, clearly exemplified by the dysfunctional but not completely inactive rFX‐251Pro variant that, albeit with severely reduced function, is compatible with a residual activity ensuring minimal haemostasis and permitting perinatal survival.

show abstract

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

Cited by 30 publications

References 18 publications

Factor X and Factor X Deficiency

Factor X and Factor X Deficiency

A Phenome-Wide Association Study Uncovers a Pathological Role of Coagulation Factor X duringAcinetobacter baumanniiInfection

Missense changes in the catalytic domain of coagulation factor X account for minimal function preventing a perinatal lethal condition

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