Trpm4-Linked Isolated Cardiac Conduction Defects

Abstract

Cardiac conduction system disease (CCD) is a common medical problem, with about 3 million people worldwide with pacemakers and 600 000 implanted each year.1 Despite its prevalence, there is little known about the molecular pathogenesis of CCD in the general population. Therefore, investigators have turned to cases of familial conduction system disease to gain insights. Article see p 374 This approach has led to the discovery of several genes involved in syndromic CCD (reviewed by Wolf and Berul).2 Mutations in the transcription factor NKX2.5 cause atrial septal defects and progressive atrioventricular block (AVB). Defects in another transcription factor, Tbx5, cause Holt-Oram syndrome, characterized by atrial septal defects, progressive AVB, and radial limb deformities. Muscular dystrophies can be associated with AVB as well. Emery-Dreifuss muscular dystrophy, whether caused by defects in Emerin or Lamin A/C, is associated with AVB, and myotonic dystrophy, caused by expansion of a trinucleotide repeat downstream of the DMPK gene, is also associated with progressive AVB. Atrioventricular block is a frequent finding in patients with PRKAG2 mutations who also have accessory atrioventricular connections and glycogen storage cardiomyopathy. Finally, AVB can be seen as part of the Andersen-Tawil syndrome of prolonged QT interval, potassium-sensitive periodic paralysis, ventricular arrhythmias, and dysmorphic features. What about isolated atrioventricular conduction disease? Until recently, the only gene implicated in human-isolated progressive CCD was the cardiac voltage-gated sodium channel, SCN5a.3 Thus, there is great interest in the causative gene recently identified in a large South African family with autosomal dominant progressive familial heart block, type I.4 …