FGF12 is a candidate Brugada syndrome locus

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Electrophysiology

Background:

• Brugada syndrome (BrS) often lacks identified genetic causes, with SCN5A and CACNA1C mutations being most common.
• Fibroblast growth factors (FGFs) homologous factors (FHFs) are known regulators of cardiac ion channels.
• FHFs are investigated as potential genetic loci for BrS.

Purpose of the Study:

• To investigate whether FGF12 serves as a candidate gene for Brugada syndrome.
• To identify and characterize mutations in FGF12 associated with BrS.

Main Methods:

• Quantitative PCR identified FGF12 as the primary FHF in the human ventricle.
• A BrS patient cohort was screened for FHF mutations.
• Biochemical and electrophysiological analyses assessed the functional impact of identified mutations.
• A novel rat cardiomyocyte system was used to evaluate mutant effects on ionic currents and action potentials.

Main Results:

• FGF12 was confirmed as the major FHF in the human ventricle.
• A novel missense mutation, Q7R-FGF12, was identified in a BrS patient.
• The Q7R-FGF12 mutation impaired binding to NaV1.5 but not junctophilin-2.
• In rat cardiomyocytes, Q7R-FGF12 reduced sodium channel current density and action potential amplitude without affecting calcium channels.

Conclusions:

• The Q7R-FGF12 mutation is strongly implicated as a cause of Brugada syndrome.
• This study demonstrates that FHF effects on sodium and calcium channels can be distinct.
• A novel methodology for analyzing arrhythmogenic mutation effects on cardiac ionic currents was established.