Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

ACC 2024 Congress

Catch up on all the top stories and latest evidence in cardiology research with our ACC 2024 Congress hub page.
ADVANCED SEARCH
Log in
Top
Heart and Vessels
Published in: Heart and Vessels 7/2018

01-07-2018 | Original Article

A mutant HCN4 channel in a family with bradycardia, left bundle branch block, and left ventricular noncompaction

Authors: Ryosuke Yokoyama, Koshi Kinoshita, Yukiko Hata, Masayoshi Abe, Kenta Matsuoka, Keiichi Hirono, Masanobu Kano, Makoto Nakazawa, Fukiko Ichida, Naoki Nishida, Toshihide Tabata

Published in: Heart and Vessels | Issue 7/2018

Login to get access

Abstract

We found that a female infant presenting with left bundle branch block and left ventricular noncompaction carries uninvestigated gene mutations HCN4(G811E), SCN5A(L1988R), DMD(S2384Y), and EMD(R203H). Here, we explored the possible pathogenicity of HCN4(G811E), which results in a G811E substitution in hyperpolarization-activated cyclic nucleotide-gated channel 4, the main subunit of the cardiac pacemaker channel. Voltage-clamp measurements in a heterologous expression system of HEK293T cells showed that HCN4(G811E) slightly reduced whole-cell HCN4 channel conductance, whereas it did not affect the gating kinetics, unitary conductance, or cAMP-dependent modulation of voltage-dependence. Immunocytochemistry and immunoblot analysis showed that the G811E mutation did not impair the membrane trafficking of the channel subunit in the heterologous expression system. These findings indicate that HCN4(G811E) may not be a monogenic factor to cause the cardiac disorders.
Appendix
Available only for authorised users
Literature
1.
Shi W, Wymore R, Yu H, Wu J, Wymore RT, Pan Z, Robinson RB, Dixon JE, McKinnon D, Cohen IS (1999) Distribution and prevalence of hyperpolarization-activated cation channel (HCN) mRNA expression in cardiac tissues. Circ Res 85:e1–e6CrossRefPubMed
2.
Verkerk AO, Wilders R (2014) Pacemaker activity of the human sinoatrial node: effects of HCN4 mutations on the hyperpolarization-activated current. Europace 16:384–395CrossRefPubMed
3.
4.
Duhme N, Schweizer PA, Thomas D, Becker R, Schroter J, Barends TR, Schlichting I, Draguhn A, Bruehl C, Katus HA, Koenen M (2013) Altered HCN4 channel C-linker interaction is associated with familial tachycardia-bradycardia syndrome and atrial fibrillation. Eur Heart J 34:2768–2775CrossRefPubMed
5.
Schweizer PA, Duhme N, Thomas D, Becker R, Zehelein J, Draguhn A, Bruehl C, Katus HA, Koenen M (2010) cAMP sensitivity of HCN pacemaker channels determines basal heart rate but is not critical for autonomic rate control. Circ Arrhythm Electrophysiol 3:542–552CrossRefPubMed
6.
Schulze-Bahr E, Neu A, Friederich P, Kaupp UB, Breithardt G, Pongs O, Isbrandt D (2003) Pacemaker channel dysfunction in a patient with sinus node disease. J Clin Investig 111:1537–1545CrossRefPubMedPubMedCentral
7.
Hategan L, Csanyi B, Ordog B, Kakonyi K, Tringer A, Kiss O, Orosz A, Saghy L, Nagy I, Hegedus Z, Rudas L, Szell M, Varro A, Forster T, Sepp R (2017) A novel ‘splice site’ HCN4 Gene mutation, c.1737 + 1 G>T, causes familial bradycardia, reduced heart rate response, impaired chronotropic competence and increased short-term heart rate variability. Int J Cardiol 241:364–372CrossRefPubMed
8.
Milano A, Vermeer AM, Lodder EM, Barc J, Verkerk AO, Postma AV, van der Bilt IA, Baars MJ, van Haelst PL, Caliskan K, Hoedemaekers YM, Le Scouarnec S, Redon R, Pinto YM, Christiaans I, Wilde AA, Bezzina CR (2014) HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy. J Am Coll Cardiol 64:745–756CrossRefPubMed
9.
Schweizer PA, Schröter J, Greiner S, Haas J, Yampolsky P, Mereles D, Buss SJ, Seyler C, Bruehl C, Draguhn A, Koenen M, Meder B, Katus HA, Thomas D (2014) The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel. J Am Coll Cardiol 64:757–767CrossRefPubMed
10.
Liang X, Evans SM, Sun Y (2015) Insights into cardiac conduction system formation provided by HCN4 expression. Trends Cardiovasc Med 25:1–9CrossRefPubMed
11.
Ichida F, Tsubata S, Bowles KR, Haneda N, Uese K, Miyawaki T, Dreyer WJ, Messina J, Li H, Bowles NE, Towbin JA (2001) Novel gene mutations in patients with left ventricular noncompaction or Barth syndrome. Circulation 103:1256–1263CrossRefPubMed
12.
Hata Y, Kinoshita K, Mizumaki K, Yamaguchi Y, Hirono K, Ichida F, Takasaki A, Mori H, Nishida N (2016) Postmortem genetic analysis of sudden unexplained death syndrome under 50 years of age: a next-generation sequencing study. Heart Rhythm 13:1544–1551CrossRefPubMed
13.
Yamaguchi Y, Nishide K, Kato M, Hata Y, Mizumaki K, Kinoshita K, Nonobe Y, Tabata T, Sakamoto T, Kataoka N, Nakatani Y, Ichida F, Mori H, Fukurotani K, Inoue H, Nishida N (2014) Glycine/serine polymorphism at position 38 influences KCNE1 subunit’s modulatory actions on rapid and slow delayed rectifier K+ currents. Circ J 78:610–618CrossRefPubMed
14.
Maekawa K, Saito Y, Ozawa S, Adachi-Akahane S, Kawamoto M, Komamura K, Shimizu W, Ueno K, Kamakura S, Kamatani N, Kitakaze M, Sawada J (2005) Genetic polymorphisms and haplotypes of the human cardiac sodium channel alpha subunit gene (SCN5A) in Japanese and their association with arrhythmia. Ann Hum Genet 69:413–428CrossRefPubMed
15.
Lee YS, Olaopa MA, Jung BC, Lee SH, Shin DG, Park HS, Cho Y, Han SM, Lee MH, Kim YN (2016) Genetic variation of SCN5A in Korean patients with sick sinus syndrome. Korean Circ J 46:63–71CrossRefPubMedPubMedCentral
16.
Hussein A, Karimianpour A, Collier P, Krasuski RA (2015) Isolated noncompaction of the left ventricle in adults. J Am Coll Cardiol 66:578–585CrossRefPubMed
17.
Ohno S, Omura M, Kawamura M, Kimura H, Itoh H, Makiyama T, Ushinohama H, Makita N, Horie M (2014) Exon 3 deletion of RYR2 encoding cardiac ryanodine receptor is associated with left ventricular non-compaction. Europace 16:1646–1654CrossRefPubMed
18.
Towbin JA, Lorts A, Jefferies JL (2015) Left ventricular non-compaction cardiomyopathy. Lancet 386(9995):813–825CrossRefPubMed
19.
Lolicato M, Bucchi A, Arrigoni C, Zucca S, Nardini M, Schroeder I, Simmons K, Aquila M, DiFrancesco D, Bolognesi M, Schwede F, Kashin D, Fishwick CW, Johnson AP, Thiel G, Moroni A (2014) Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness. Nat Chem Biol 10:457–462CrossRefPubMed
20.
21.
Liao Z, Lockhead D, St Clair JR, Larson ED, Wilson CE, Proenza C (2012) Cellular context and multiple channel domains determine cAMP sensitivity of HCN4 channels: ligand-independent relief of autoinhibition in HCN4. J Gen Physiol 140:557–566CrossRefPubMedPubMedCentral
22.
DiFrancesco D, Tortora P (1991) Direct activation of cardiac pacemaker channels by intracellular cyclic AMP. Nature 351:145–147CrossRefPubMed
23.
24.
Laish-Farkash A, Glikson M, Brass D, Marek-Yagel D, Pras E, Dascal N, Antzelevitch C, Nof E, Reznik H, Eldar M, Luria D (2010) A novel mutation in the HCN4 gene causes symptomatic sinus bradycardia in Moroccan Jews. J Cardiovasc Electrophysiol 21:1365–1372CrossRefPubMedPubMedCentral
25.
Macri V, Mahida SN, Zhang ML, Sinner MF, Dolmatova EV, Tucker NR, McLellan M, Shea MA, Milan DJ, Lunetta KL, Benjamin EJ, Ellinor PT (2014) A novel trafficking-defective HCN4 mutation is associated with early-onset atrial fibrillation. Heart Rhythm 11:1055–1062CrossRefPubMedPubMedCentral
26.
Nof E, Luria D, Brass D, Marek D, Lahat H, Reznik-Wolf H, Pras E, Dascal N, Eldar M, Glikson M (2007) Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia. Circulation 116:463–470CrossRefPubMed
27.
Baruscotti M, Barbuti A, Bucchi A (2010) The cardiac pacemaker current. J Mol Cell Cardiol 48:55–64CrossRefPubMed
28.
Ferlini A, Neri M, Gualandi F (2013) The medical genetics of dystrophinopathies: molecular genetic diagnosis and its impact on clinical practice. Neuromuscul Disord 23:4–14CrossRefPubMed
29.
Arbustini E, Weidemann F, Hall JL (2014) Left ventricular noncompaction: a distinct cardiomyopathy or a trait shared by different cardiac diseases? J Am Coll Cardiol 64:1840–1850CrossRefPubMed
30.
Kimura K, Morita H, Daimon M, Kawata T, Nakao T, Lee SL, Hirokawa M, Ebihara A, Nakajima T, Ozawa T, Yonemochi Y, Aida I, Motoyoshi Y, Mikata T, Uchida I, Komori T, Kitao R, Nagata T, Takeda S, Komaki H, Segawa K, Takenaka K, Komuro I (2015) Prognostic impact of venous thromboembolism in patients with Duchenne muscular dystrophy: prospective multicenter 5-year cohort study. Int J Cardiol 191:178–180CrossRefPubMed
31.
Parent JJ, Moore RA, Taylor MD, Towbin JA, Jefferies JL (2015) Left ventricular noncompaction cardiomyopathy in Duchenne muscular dystrophy carriers. J Cardiol Cases 11:7–9CrossRef
32.
Meinke P, Nguyen TD, Wehnert MS (2011) The LINC complex and human disease. Biochem Soc Trans 39:1693–1697CrossRefPubMed
33.
Yuan J, Xue B (2015) Role of structural flexibility in the evolution of emerin. J Theor Biol 385:102–111CrossRefPubMed
34.
Parmar MS, Parmar KS (2012) Emery-Dreifuss humeroperoneal muscular dystrophy: cardiac manifestations. Can J Cardiol 28(4):516.e1–516.e3CrossRef
35.
Monserrat L, Hermida-Prieto M, Fernandez X, Rodríguez I, Dumont C, Cazón L, Cuesta MG, Gonzalez-Juanatey C, Peteiro J, Álvarez N, Penas-Lado M, Castro-Beiras A (2007) Mutation in the alpha-cardiac actin gene associated with apical hypertrophic cardiomyopathy, left ventricular non-compaction, and septal defects. Eur Heart J 28:1953–1961CrossRefPubMed
36.
Girolami F, Iascone M, Tomberli B, Bardi S, Benelli M, Marseglia G, Pescucci C, Pezzoli L, Sana ME, Basso C, Marziliano N, Merlini PA, Fornaro A, Cecchi F, Torricelli F, Olivotto I (2014) Novel alpha-actinin 2 variant associated with familial hypertrophic cardiomyopathy and juvenile atrial arrhythmias: a massively parallel sequencing study. Circ Cardiovasc Genet 7:741–750CrossRefPubMed
37.
38.
Williams T, Machann W, Kuhler L, Hamm H, Muller-Hocker J, Zimmer M, Ertl G, Ritter O, Beer M, Schonberger J (2011) Novel desmoplakin mutation: juvenile biventricular cardiomyopathy with left ventricular non-compaction and acantholytic palmoplantar keratoderma. Clin Res Cardiol 100:1087–1093CrossRefPubMedPubMedCentral
39.
Blinder JJ, Martinez HR, Craigen WJ, Belmont J, Pignatelli RH, Jefferies JL (2011) Noncompaction of the left ventricular myocardium in a boy with a novel chromosome 8p23.1 deletion. Am J Med Genet A 155A:2215–2220CrossRefPubMed
40.
Vatta M, Mohapatra B, Jimenez S, Sanchez X, Faulkner G, Perles Z, Sinagra G, Lin JH, Vu TM, Zhou Q, Bowles KR, Di Lenarda A, Schimmenti L, Fox M, Chrisco MA, Murphy RT, McKenna W, Elliott P, Bowles NE, Chen J, Valle G, Towbin JA (2003) Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction. J Am Coll Cardiol 42:2014–2027CrossRefPubMed
41.
Liu Z, Shan H, Huang J, Li N, Hou C, Pu J (2016) A novel lamin A/C gene missense mutation (445 V > E) in immunoglobulin-like fold associated with left ventricular non-compaction. Europace 18:617–822CrossRefPubMed
42.
Wessels MW, Herkert JC, Frohn-Mulder IM, Dalinghaus M, van den Wijngaard A, de Krijger RR, Michels M, de Coo IF, Hoedemaekers YM, Dooijes D (2015) Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects. Eur J Hum Genet 23:922–928CrossRefPubMed
43.
Hoedemaekers YM, Caliskan K, Majoor-Krakauer D, van de Laar I, Michels M, Witsenburg M, ten Cate FJ, Simoons ML, Dooijes D (2007) Cardiac beta-myosin heavy chain defects in two families with non-compaction cardiomyopathy: linking non-compaction to hypertrophic, restrictive, and dilated cardiomyopathies. Eur Heart J 28:2732–2737CrossRefPubMed
44.
Ouyang P, Saarel E, Bai Y, Luo C, Lv Q, Xu Y, Wang F, Fan C, Younoszai A, Chen Q, Tu X, Wang QK (2011) A de novo mutation in NKX2.5 associated with atrial septal defects, ventricular noncompaction, syncope and sudden death. Clin Chim Acta 412:170–175CrossRefPubMed
45.
Hoedemaekers YM, Caliskan K, Michels M, Frohn-Mulder I, van der Smagt JJ, Phefferkorn JE, Wessels MW, ten Cate FJ, Sijbrands EJ, Dooijes D, Majoor-Krakauer DF (2010) The importance of genetic counseling, DNA diagnostics, and cardiologic family screening in left ventricular noncompaction cardiomyopathy. Circ Cardiovasc Genet 3:232–239CrossRefPubMed
46.
Shan L, Makita N, Xing Y, Watanabe S, Futatani T, Ye F, Saito K, Ibuki K, Watanabe K, Hirono K, Uese K, Ichida F, Miyawaki T, Origasa H, Bowles NE, Towbin JA (2008) SCN5A variants in Japanese patients with left ventricular noncompaction and arrhythmia. Mol Genet Metab 93:468–474CrossRefPubMed
47.
Ronvelia D, Greenwood J, Platt J, Hakim S, Zaragoza MV (2012) Intrafamilial variability for novel TAZ gene mutation: Barth syndrome with dilated cardiomyopathy and heart failure in an infant and left ventricular noncompaction in his great-uncle. Mol Genet Metab 107:428–432CrossRefPubMedPubMedCentral
48.
Kapadia R, Choudhary P, Collins N, Celermajer D, Puranik R (2016) Left ventricular non-compaction in Holt–Oram syndrome. Heart Lung Circ 25:626–630CrossRefPubMed
49.
Luedde M, Ehlermann P, Weichenhan D, Will R, Zeller R, Rupp S, Müller A, Steen H, Ivandic BT, Ulmer HE, Kern M, Katus HA, Frey N (2010) Severe familial left ventricular non-compaction cardiomyopathy due to a novel troponin T (TNNT2) mutation. Cardiovasc Res 86:452–460CrossRefPubMed
50.
Chang B, Nishizawa T, Furutani M, Fujiki A, Tani M, Kawaguchi M, Ibuki K, Hirono K, Taneichi H, Uese K, Onuma Y, Bowles NE, Ichida F, Inoue H, Matsuoka R, Miyawaki T, Noncompaction Study C (2011) Identification of a novel TPM1 mutation in a family with left ventricular noncompaction and sudden death. Mol Genet Metab 102:200–206CrossRefPubMed
51.
Graham TP Jr, Jarmakani JM, Canent RV Jr, Morrow MN (1971) Left heart volume estimation in infancy and childhood. Reevaluation of methodology and normal values. Circulation 43:895–904CrossRefPubMed
Metadata
Title
A mutant HCN4 channel in a family with bradycardia, left bundle branch block, and left ventricular noncompaction
Authors
Ryosuke Yokoyama
Koshi Kinoshita
Yukiko Hata
Masayoshi Abe
Kenta Matsuoka
Keiichi Hirono
Masanobu Kano
Makoto Nakazawa
Fukiko Ichida
Naoki Nishida
Toshihide Tabata
Publication date
01-07-2018
Publisher
Springer Japan
Published in
Heart and Vessels / Issue 7/2018
Print ISSN: 0910-8327
Electronic ISSN: 1615-2573
DOI
https://doi.org/10.1007/s00380-018-1116-6

Other articles of this Issue 7/2018

Heart and Vessels 7/2018 Go to the issue

Original Article

Portal congestion and intestinal edema in hospitalized patients with heart failure

Original Article

The impact of non-alcoholic fatty liver disease fibrosis score on cardiac prognosis in patients with chronic heart failure

Original Article

Atrial fibrillation diagnosed by a medical checkup is associated with a poor outcome of catheter ablation

Short Communication

Influence of dietary iron intake restriction on the development of hypertension in weanling prehypertensive rats

Original Article

High-intensity aerobic interval training can lead to improvement in skeletal muscle power among in-hospital patients with advanced heart failure

Original Article

Suppression of aortic expansion and contractile recovery in a rat abdominal aortic aneurysm model by biodegradable gelatin hydrogel sheet incorporating basic fibroblast growth factor

ACC 2024 Congress Coverage

Cardiology Video

Highlights from the ACC 2024 Congress

Watch now

Watch official videos from the ACC congress summarizing key highlights from the last year in heart failure, cardiomyopathies, valvular disease, pulmonary vascular disease, and pediatric cardiology.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits