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


RESULTS
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.


CONCLUSIONS
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.
Department of Pharmacology, Medical School of Xi'an Jiaotong University.
Jun
J
Zhou
Wei-Guang
WG
Ding
Takeru
T
Makiyama
Akashi
A
Miyamoto
Yuichi
Y
Matsumoto
Hiromi
H
Kimura
Yasuhiro
Y
Tarutani
Jin
J
Zhao
Jie
J
Wu
Wei-Jin
WJ
Zang
Hiroshi
H
Matsuura
Minoru
M
Horie
D000368:Aged; D019943:Amino Acid Substitution; D054537:Atrioventricular Block / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism
C119587:HCN4 protein, human; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D009124:Muscle Proteins; D015221:Potassium Channels