Combined cis-regulator elements as important mechanism affecting FXII plasma levels

Maria Sabater-Lleal, Miguel Chillón, Carolina Mordillo, Ángel Martínez, Estel Gil, José Mateo, John Blangero, Laura Almasy, Jordi Fontcuberta, José Manuel Soria

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Introduction: Factor XII (FXII) deficiency is a recessive Mendelian trait due to mutations in the F12 gene. There is no bleeding associated with FXII deficiency, but FXII deficiency has been reported to be associated with risk of thrombosis in some studies. Material and Methods: We examined the functional effect of two naturally-occurring mutations in two Spanish FXII deficient families: a C/G substitution at position -8, and a C/T substitution at position -13. Both mutations were located on a putative HNF4 binding site of F12 gene promoter. We also analyzed the F12 C46T polymorphism (rs1801020), associated with a decrease in the FXII levels, which also segregated in both families. A fragment containing each one of both -8 and -13 mutations, was cloned 5′ of a reporter gene. We compared the in vitro expression of these constructs to the wild type expression. Results: Our analyses confirm that the -8C/G and the -13C/T mutations decreased expression levels, demonstrating that both mutations are involved in the observed FXII deficiency. In addition, electrophoretic shift analyses suggest that they alter the union of nuclear proteins to the promoter. Coinheritance of these mutations with the C46T polymorphism, result in a significant genotype-phenotype correlation. Conclusions: We have identified two naturally-occurring mutations in the F12 promoter that drastically reduce FXII levels. Knowing rare genetic alterations in the F12 gene, together with the C46T common variant, may yield further understanding about the genetic architecture of FXII levels, which may have a role in the risk of thrombosis.

Original languageEnglish (US)
JournalThrombosis Research
Volume125
Issue number2
DOIs
StatePublished - Feb 2010
Externally publishedYes

Fingerprint

Factor XII
Factor XII Deficiency
Mutation
Thrombosis
Genes
Genetic Association Studies
Nuclear Proteins
Reporter Genes
Binding Sites
Hemorrhage

Keywords

  • F12
  • Genetic analyses
  • Promoter expression
  • Thrombophilia

ASJC Scopus subject areas

  • Hematology

Cite this

Sabater-Lleal, M., Chillón, M., Mordillo, C., Martínez, Á., Gil, E., Mateo, J., ... Soria, J. M. (2010). Combined cis-regulator elements as important mechanism affecting FXII plasma levels. Thrombosis Research, 125(2). https://doi.org/10.1016/j.thromres.2009.08.019

Combined cis-regulator elements as important mechanism affecting FXII plasma levels. / Sabater-Lleal, Maria; Chillón, Miguel; Mordillo, Carolina; Martínez, Ángel; Gil, Estel; Mateo, José; Blangero, John; Almasy, Laura; Fontcuberta, Jordi; Soria, José Manuel.

In: Thrombosis Research, Vol. 125, No. 2, 02.2010.

Research output: Contribution to journalArticle

Sabater-Lleal, M, Chillón, M, Mordillo, C, Martínez, Á, Gil, E, Mateo, J, Blangero, J, Almasy, L, Fontcuberta, J & Soria, JM 2010, 'Combined cis-regulator elements as important mechanism affecting FXII plasma levels', Thrombosis Research, vol. 125, no. 2. https://doi.org/10.1016/j.thromres.2009.08.019
Sabater-Lleal, Maria ; Chillón, Miguel ; Mordillo, Carolina ; Martínez, Ángel ; Gil, Estel ; Mateo, José ; Blangero, John ; Almasy, Laura ; Fontcuberta, Jordi ; Soria, José Manuel. / Combined cis-regulator elements as important mechanism affecting FXII plasma levels. In: Thrombosis Research. 2010 ; Vol. 125, No. 2.
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N2 - Introduction: Factor XII (FXII) deficiency is a recessive Mendelian trait due to mutations in the F12 gene. There is no bleeding associated with FXII deficiency, but FXII deficiency has been reported to be associated with risk of thrombosis in some studies. Material and Methods: We examined the functional effect of two naturally-occurring mutations in two Spanish FXII deficient families: a C/G substitution at position -8, and a C/T substitution at position -13. Both mutations were located on a putative HNF4 binding site of F12 gene promoter. We also analyzed the F12 C46T polymorphism (rs1801020), associated with a decrease in the FXII levels, which also segregated in both families. A fragment containing each one of both -8 and -13 mutations, was cloned 5′ of a reporter gene. We compared the in vitro expression of these constructs to the wild type expression. Results: Our analyses confirm that the -8C/G and the -13C/T mutations decreased expression levels, demonstrating that both mutations are involved in the observed FXII deficiency. In addition, electrophoretic shift analyses suggest that they alter the union of nuclear proteins to the promoter. Coinheritance of these mutations with the C46T polymorphism, result in a significant genotype-phenotype correlation. Conclusions: We have identified two naturally-occurring mutations in the F12 promoter that drastically reduce FXII levels. Knowing rare genetic alterations in the F12 gene, together with the C46T common variant, may yield further understanding about the genetic architecture of FXII levels, which may have a role in the risk of thrombosis.

AB - Introduction: Factor XII (FXII) deficiency is a recessive Mendelian trait due to mutations in the F12 gene. There is no bleeding associated with FXII deficiency, but FXII deficiency has been reported to be associated with risk of thrombosis in some studies. Material and Methods: We examined the functional effect of two naturally-occurring mutations in two Spanish FXII deficient families: a C/G substitution at position -8, and a C/T substitution at position -13. Both mutations were located on a putative HNF4 binding site of F12 gene promoter. We also analyzed the F12 C46T polymorphism (rs1801020), associated with a decrease in the FXII levels, which also segregated in both families. A fragment containing each one of both -8 and -13 mutations, was cloned 5′ of a reporter gene. We compared the in vitro expression of these constructs to the wild type expression. Results: Our analyses confirm that the -8C/G and the -13C/T mutations decreased expression levels, demonstrating that both mutations are involved in the observed FXII deficiency. In addition, electrophoretic shift analyses suggest that they alter the union of nuclear proteins to the promoter. Coinheritance of these mutations with the C46T polymorphism, result in a significant genotype-phenotype correlation. Conclusions: We have identified two naturally-occurring mutations in the F12 promoter that drastically reduce FXII levels. Knowing rare genetic alterations in the F12 gene, together with the C46T common variant, may yield further understanding about the genetic architecture of FXII levels, which may have a role in the risk of thrombosis.

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