Published Online
on July 23, 2007

A more recent version of this article appeared on July 31, 2007

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Submitted on April 5, 2007
Accepted on May 29, 2007

Point Mutation in the HCN4 Cardiac Ion Channel Pore Affecting Synthesis, Trafficking, and Functional Expression Is Associated With Familial Asymptomatic Sinus Bradycardia

Eyal Nof MD^*, David Luria MD, Dovrat Brass MSc, Dina Marek MSc, Hadas Lahat PhD, Haya Reznik-Wolf PhD, Elon Pras MD, Nathan Dascal PhD, Michael Eldar MD, and Michael Glikson MD

From the Heart Institute (E.N., D.L., M.E., M.G.) and Laboratory of Human Genetics (D.M., H.L., H.R.-W., E.P.), Chaim Sheba Medical Center, Tel-Hashomer; Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (D.B., N.D.); and Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Bar Ilan (D.M.), Israel.

^* To whom correspondence should be addressed. E-mail: ernof{at}netvision.net.il.

Background--The hyperpolarization-activated nucleotide-gated channel-HCN4 plays a major role in the diastolic depolarization of sinus atrial node cells. Mutant HCN4 channels have been found to be associated with inherited sinus bradycardia.

Methods and Results--Sixteen members of a family with sinus bradycardia were evaluated. Evaluation included a clinical questionnaire, 12-lead ECGs, Holter monitoring, echocardiography, and treadmill exercise testing. Eight family members (5 males) were classified as affected. All affected family members were asymptomatic with normal exercise capacity during long-term follow-up. Electrophysiological testing performed on 2 affected family members confirmed significant isolated sinus node dysfunction. Segregation analysis suggested autosomal-dominant inheritance. Direct sequencing of the exons encoding HCN4 revealed a missense mutation, G480R, in the ion channel pore domain in all affected family members. Function analysis, including expression of HCN4 wild-type and G480R in Xenopus oocytes and human embryonic kidney 293 cells, revealed that mutant channels were activated at more negative voltages compared with wild-type channels. Synthesis and expression of the wild-type and mutant HCN4 channel on the plasma membrane tested in human embryonic kidney 293 cells using biotinylation and Western blot analysis demonstrated a reduction in synthesis and a trafficking defect in mutant compared with wild-type channels.

Conclusions--We describe an inherited, autosomal-dominant form of sinus node dysfunction caused by a missense mutation in the HCN4 ion channel pore. Despite its critical location, this mutation carries a favorable prognosis without the need for pacemaker implantation during long-term follow-up.

Key words: bradycardia • genetics • ion channels

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