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(Circulation. 2007;116:463-470.)
© 2007 American Heart Association, Inc.

Arrhythmia/Electrophysiology

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; 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.

Correspondence to Eyal Nof, MD, Heart Institute, Sheba Medical Center, Tel Hashomer 52621 Israel. E-mail ernof{at}netvision.net.il

Received April 5, 2007; accepted May 29, 2007.

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.

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