Multifocal ectopic Purkinje-related premature contractions: a new SCN5A-related cardiac channelopathy.

OBJECTIVES: The aim of this study was to describe a new familial cardiac phenotype and to elucidate the electrophysiological mechanism responsible for the disease. BACKGROUND: Mutations in several genes encoding ion channels, especially SCN5A, have emerged as the basis for a variety of inherited cardiac arrhythmias. METHODS: Three unrelated families comprising 21 individuals affected by multifocal ectopic Purkinje-related premature contractions (MEPPC) characterized by narrow junctional and rare sinus beats competing with numerous premature ventricular contractions with right and/or left bundle branch block patterns were identified. RESULTS: Dilated cardiomyopathy was identified in 6 patients, atrial arrhythmias were detected in 9 patients, and sudden death was reported in 5 individuals. Invasive electrophysiological studies demonstrated that premature ventricular complexes originated from the Purkinje tissue. Hydroquinidine treatment dramatically decreased the number of premature ventricular complexes. It normalized the contractile function in 2 patients. All the affected subjects carried the c.665G>A transition in the SCN5A gene. Patch-clamp studies of resulting p.Arg222Gln (R222Q) Nav1.5 revealed a net gain of function of the sodium channel, leading, in silico, to incomplete repolarization in Purkinje cells responsible for premature ventricular action potentials. In vitro and in silico studies recapitulated the normalization of the ventricular action potentials in the presence of quinidine. CONCLUSIONS: A new SCN5A-related cardiac syndrome, MEPPC, was identified. The SCN5A mutation leads to a gain of function of the sodium channel responsible for hyperexcitability of the fascicular-Purkinje system. The MEPPC syndrome is responsive to hydroquinidine.

MicroRNAs and the kidney: coming of age.

PURPOSE OF REVIEW: MicroRNAs (miRNAs) are regulatory RNAs that act as posttranscriptional repressors by binding the 3' untranslated region of target genes. They have been implicated in diverse biologic and pathologic processes and are emerging as important players in kidney health and disease. Here, we review the latest literature in this exciting and rapidly evolving field. RECENT FINDINGS: Studies of conditional Dicer knockout mice revealed critical roles for miRNAs in orchestrating kidney development and maintaining the structural and functional integrity of the renal collecting system and glomerular barrier. Expression profiling has provided a reasonably clear picture of miRNAs present in normal kidney and pointed to individual miRNAs that may serve special functional roles therein. Specific miRNAs have been implicated in pathways linked to cystic kidney disease (miR-15a), and Wilms' tumor (miR-17-92). Several miRNAs are upregulated by transforming growth factor beta-1 in models of diabetic nephropathy. Some promote matrix deposition (miR-192 and miR-377) or epithelial-to-mesenchymal transition (miR-200 and miR-205), whereas preliminary findings suggest others might serve protective roles (miR-21). miRNAs recently identified in urinary exosomes could potentially serve as disease biomarkers. SUMMARY: Nephrology is in the midst of a miRNA 'revolution' that promises incredible advances in our understanding of genetic regulatory pathways underlying kidney disease, and, with it, new avenues for treatment.