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A novel HCN4 mutation, G1097W, is associated with atrioventricular block.
- Source :
-
Circulation journal : official journal of the Japanese Circulation Society [Circ J] 2014; Vol. 78 (4), pp. 938-42. Date of Electronic Publication: 2014 Jan 31. - Publication Year :
- 2014
-
Abstract
- 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.<br />Methods and 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.<br />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.
- Subjects :
- Aged
Amino Acid Substitution
Female
Humans
Male
Middle Aged
Mutation, Missense
Atrioventricular Block genetics
Atrioventricular Block mortality
Atrioventricular Block pathology
Atrioventricular Block physiopathology
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels genetics
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels metabolism
Muscle Proteins genetics
Muscle Proteins metabolism
Potassium Channels genetics
Potassium Channels metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1347-4820
- Volume :
- 78
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Circulation journal : official journal of the Japanese Circulation Society
- Publication Type :
- Academic Journal
- Accession number :
- 24492017
- Full Text :
- https://doi.org/10.1253/circj.cj-13-0996