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

Area of Science:

• Genetics
• Molecular Biology
• Hematology

Background:

• Factor XII (FXII) deficiency is a genetic disorder linked to F12 gene mutations.
• While typically asymptomatic, FXII deficiency has been anecdotally associated with increased thrombosis risk.
• The genetic underpinnings of FXII levels and their clinical implications, particularly thrombosis risk, require further elucidation.

Purpose of the Study:

• To investigate the functional impact of two specific F12 gene promoter mutations found in Spanish families with FXII deficiency.
• To analyze the role of these mutations and a common F12 C46T polymorphism in determining FXII levels.
• To establish genotype-phenotype correlations related to FXII deficiency and potential thrombosis risk.

Main Methods:

• Examined two naturally occurring mutations (-8C/G and -13C/T) in the F12 gene promoter in Spanish families.
• Assessed the impact of these mutations on gene expression using reporter gene constructs in vitro.
• Analyzed the F12 C46T polymorphism (rs1801020) and performed electrophoretic shift assays.

Main Results:

• Confirmed that the -8C/G and -13C/T mutations significantly decrease F12 gene expression.
• Demonstrated that these mutations alter nuclear protein binding to the F12 promoter.
• Observed a significant genotype-phenotype correlation when these mutations co-occurred with the C46T polymorphism.

Conclusions:

• Identified two novel F12 promoter mutations that markedly reduce FXII levels.
• These findings contribute to understanding the genetic basis of FXII levels.
• Combined knowledge of rare F12 mutations and common variants like C46T may refine risk assessment for thrombosis.