Referenced in: none

Automatically associated channels: HCN3 , HCN4

Title: A novel HCN4 mutation, G1097W, is associated with atrioventricular block.

Authors: Jun Zhou, Wei-Guang Ding, Takeru Makiyama, Akashi Miyamoto, Yuichi Matsumoto, Hiromi Kimura, Yasuhiro Tarutani, Jin Zhao, Jie Wu, Wei-Jin Zang, Hiroshi Matsuura, Minoru Horie

Journal, date & volume: Circ. J., 2014 , 78, 938-42

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/24492017

Abstract
 Loss-of-function mutations in the HCN4 gene have been shown to be associated with sinus dysfunction, but there are no reports on HCN4-mediated atrioventricular (AV) block. A novel missense HCN4 mutation G1097W was identified in a 69 year-old Japanese male with AV block, and we characterized the functional consequences of If-like channels reconstituted with the heterozygous HCN4 mutation. Wild-type (WT) HCN4 or/and HCN4-G1097W were expressed in a heterologous cell expression system. A functional assay using a whole-cell patch-clamp demonstrated that the mutant If-like currents were activated at more negative voltages compared to WT currents, while they retained the sensitivity to changes in intracellular cyclic adenosine monophosphate (cAMP) levels. Co-expression of G1097W with WT channels showed dominant-negative effects, including a reduction in peak currents and a negative voltage shifting on reconstituted currents. The HCN4-G1097W mutant channels displayed a loss-of-function type modulation on cardiac If channels and thus could predispose them to AV nodal dysfunction. These data provide a novel insight into the genetic basis for the AV block.