Progressive Atrial Conduction Defects Associated With Bone Malformation Caused by a Connexin-45 Mutation

Area of Science:

• Genetics
• Cardiology
• Developmental Biology

Background:

• Inherited cardiac conduction disease involves rare bradyarrhythmias due to gene mutations affecting heart electrical activity.
• It typically presents as isolated His-Purkinje system conduction disturbances, rarely as a syndromic form.

Purpose of the Study:

• To identify the genetic cause of a novel bradyarrhythmia syndrome with associated bone malformations.
• Investigate the functional impact of identified mutations on cardiac conduction.

Main Methods:

• Whole-exome sequencing of European families with de novo atrioventricular (AV) block.
• Targeted sequencing of Japanese families with familial AV block or sick sinus syndrome.
• In vitro cell expression and in vivo knockout mouse models to assess mutation effects.

Main Results:

• Identified a connexin-45 (Cx45) mutation (p.R75H) in two families with progressive AV block and atrial standstill.
• Affected individuals exhibited craniofacial, finger, and dental malformations.
• Mutant Cx45 impaired gap junction communication, and cardiac-specific knockout mice showed sinus node dysfunction and atrial arrhythmias.

Conclusions:

• The Cx45 p.R75H mutation is responsible for a new disease entity characterized by progressive atrial conduction defects.
• This condition is associated with craniofacial and dentodigital malformations, highlighting connexin-45's role in cardiac and developmental processes.