Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I

Area of Science:

• Cardiology
• Genetics
• Molecular Biology

Background:

• Progressive familial heart block type I (PFHBI) is an autosomal-dominant disorder affecting the His-Purkinje system.
• Previous research has linked PFHBI to genetic mutations, but the specific molecular mechanisms remain incompletely understood.

Purpose of the Study:

• To identify the genetic cause of autosomal-dominant PFHBI in a South African Afrikaner pedigree.
• To elucidate the functional consequences of the identified mutation in the TRPM4 gene.

Main Methods:

• Genetic analysis of affected individuals from a large pedigree.
• Identification of a specific mutation (c.19G-->A) in the TRPM4 gene.
• In vitro cellular expression studies to assess channel function and trafficking.

Main Results:

• A novel missense mutation, p.E7K, was identified in the TRPM4 gene in individuals with PFHBI.
• TRPM4 mRNA expression is highest in Purkinje fibers, suggesting a critical role in cardiac conduction.
• The mutation attenuated deSUMOylation, leading to constitutive SUMOylation, impaired endocytosis, and increased cell surface TRPM4 channel density.

Conclusions:

• The identified TRPM4 mutation causes a gain-of-function, leading to PFHBI.
• Altered TRPM4 channel trafficking and density contribute to the pathogenesis of familial heart block.
• TRPM4 is a key determinant of cardiac electrical activity in the His-Purkinje system.