POPDC2 a novel susceptibility gene for conduction disorders

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Ion Channel Physiology

Background:

• Inherited cardiac conduction disorders, such as atrioventricular block (AVB), often have an unresolved molecular basis.
• Understanding the genetic underpinnings of arrhythmias is crucial for diagnosis and treatment.

Purpose of the Study:

• To identify the genetic cause of familial atrioventricular block (AVB) using whole exome sequencing (WES).
• To investigate the functional consequences of identified mutations on cardiac ion channel function.

Main Methods:

• Whole exome sequencing (WES) in families with AVB.
• Quantitative PCR to assess gene expression in human heart tissue.
• Xenopus oocyte co-expression studies to analyze protein function.
• Generation and analysis of POPDC2 knock-in mouse models.

Main Results:

• A heterozygous nonsense mutation (POPDC2^W188⁎) in the POPDC2 gene was identified in families with AVB.
• POPDC2^W188⁎ mutation leads to loss-of-function and impaired modulation of the TREK-1 potassium channel.
• POPDC2 is highly expressed in the sinoatrial node, and POPDC2^W188⁎ knock-in mice exhibit sinus bradycardia and pauses.

Conclusions:

• The POPDC2^W188⁎ mutation contributes to AVB pathogenesis through aberrant modulation of TREK-1.
• POPDC2 is identified as a novel arrhythmia gene implicated in cardiac conduction disorders.
• This finding advances the understanding of the molecular basis of familial AVB.