* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Ion Channel Dysfunction Associated With Arrhythmia
Survey
Document related concepts
Neuronal ceroid lipofuscinosis wikipedia , lookup
Saethre–Chotzen syndrome wikipedia , lookup
Nicotinic acid adenine dinucleotide phosphate wikipedia , lookup
Therapeutic gene modulation wikipedia , lookup
Gene expression programming wikipedia , lookup
Epigenetics of neurodegenerative diseases wikipedia , lookup
Protein moonlighting wikipedia , lookup
Microevolution wikipedia , lookup
Oncogenomics wikipedia , lookup
Transcript
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 64, NO. 8, 2014 ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00 PUBLISHED BY ELSEVIER INC. http://dx.doi.org/10.1016/j.jacc.2014.06.1154 EDITORIAL COMMENT Ion Channel Dysfunction Associated With Arrhythmia, Ventricular Noncompaction, and Mitral Valve Prolapse A New Overlapping Phenotype* Jeffrey A. Towbin, MD I n this issue of the Journal, 2 elegant papers of-function mutation, located within the highly report the association of arrhythmia, primarily conserved GYG motif of the channel pore domain sinus bradycardia, left ventricular noncompac- that segregated with all affected members in the tion (LVNC), and mitral valve prolapse (MVP) (1,2), 4-generation index family (5). The common W4R demonstrating that the underlying cause is muta- variant in the cysteine and glycine-rich protein 3 tion hyperpolarization- (CSRP3) gene encoding a Z-disk protein, previously activated cyclic nucleotide channel 4 (HCN4), a and dysfunction of the reported in patients with dilated cardiomyopathy major constituent of the pacemaker current (If) in (DCM) and hypertrophic cardiomyopathy, and healthy the sinoatrial node (SAN) (3). The investigators SEE PAGES 745 AND 757 demonstrate abnormalities in channel subjects also was identified (6,7). In addition to the index family, a second unrelated family and the unrelated proband were shown to have truncation function (HCN-695X) and missense (HCN-P883R) HCN4 muta- consistent with the arrhythmia phenotype and spec- tions with no mutations identified in CSRP3. Family ulate as to the underlying pathogenesis that leads to members and probands of all 3 families had severe LVNC, a heterogeneous myocardial phenotype asso- SND with or without atrial or ventricular arrhythmias, ciated with abnormal trabeculation of the LV (4). syncope, or sudden death and a normal QTc interval. Uncertainty, however, belies the question of how Noninvasive do mutations in this ion channel cause the com- hypertrabeculation/LVNC bined phenotype. To develop a plausible hypo- studies demonstrated no hyperpolarization-activated thesis, understanding the data reported by these 2 inward currents in mutant HCN4-G482R subunits, studies, as well as a review of prior studies, is consistent with loss of function. Homozygous HCN4- required. G482R channels were nonfunctional, and hetero- Schweizer et al. (1) identify HCN4 mutations in 2 imaging demonstrated and MVP. biventricular Patch-clamp meric mutant and wild-type HCN4 channel subunits unrelated families and an additional unrelated pro- had band with sinus node dysfunction (SND)/brady- dominant-negative mechanism, resulting in If current cardia, LVNC, and MVP. Using a candidate gene reduction approach, they identified a novel HCN4-G482R loss- densities. 65% current in reduction, heterozygotes consistent and lower with a current Milano et al. (2) report on 4 families with SND with or without syncope/cardiac arrest, ventricular arrhythmias, and atrial arrhythmias, with echocar*Editorials published in the Journal of the American College of Cardiology diography demonstrating LVNC with or without reflect the views of the authors and do not necessarily represent the MVP. HCN4 mutations were identified in all fam- views of JACC or the American College of Cardiology. From The Heart Institute, Division of Pediatric Cardiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio. Dr. Towbin has ilies (Tyr481His in 2 families, Gly482Arg and Ala414Gly in 1 family each). All mutations affected reported that he has no relationships relevant to the contents of this conserved residues with 2 mutations (Tyr481His, paper to disclose. Gly482Arg) affecting highly conserved residues Towbin JACC VOL. 64, NO. 8, 2014 HCN4 and Ventricular Noncompaction AUGUST 26, 2014:768–71 within the pore domain of HCN4 and the other the (Ala414Gly) affecting the cytoplasmic S4–S5 linker machinery and ion-conducting pore; 2) the cytosolic transmembrane core harboring the gating of HCN4. Heterologous expression studies with the NH 2-terminal domain; and 3) the COOH-terminal Tyr481His and Gly482Arg mutations demonstrated a domain with the cyclic nucleotide binding domain large negative shift of the voltage dependence of and the peptide connecting the CNBD with the activation compared with expression of wild-type transmembrane core (the “C-linker”) that confers channels, indicating the importance of the pore modulation by cyclic nucleotides. The I f current is region for the voltage dependence of activation. All important in the initiation and regulation of the mutations resulted in significantly lower HCN4 heartbeat, which is therefore called the “pacemaker current density. current.” Mutation in the HCN4 gene, located on Together, these studies demonstrate that HCN4 chromosome 15q24.1, was first reported by Schulze- mutations result in loss of function and significantly Bahr et al. (10) in a patient with SND, atrial fibril- reduced If current density associated with brady- lation, and chronotropic incompetence. The 1-bp cardia, arrhythmias, and LVNC with or without MVP. deletion mutation (HCN4-573X) resulted in a pre- Conceptually, these findings are consistent with the mature stop codon and a C-terminus lacking the “final common pathway” hypothesis proposed nearly CNBD domain. In vitro heterologous expression 15 years ago, which suggested that mutations in revealed a dominant-negative loss of cAMP modu- genes encoding proteins within the same path- lation. Several other publications demonstrating way (or secondary disturbance of protein function SND with severe bradycardia, with or without atrial as a result of binding partner abnormalities, drugs, fibrillation or ventricular arrhythmias, have now and so on) leads to a common phenotype (8). This been reported. These findings with HCN4 mutations hypothesis enabled successful targeted candidate would be predicted by the “final common pathway” gene screening for arrhythmias, cardiomyopathies, hypothesis: ion channels cause rhythm disturbance. and congenital heart disease (CHD), leading to the However, Schweizer et al. (1) and Milano et al. (2) current understanding that arrhythmias are caused report the additional phenotypes of LVNC and MVP by disturbed ion channel function (“ion channelo- that would not be predicted to result solely from an pathies”), hypertrophic cardiomyopathy by disturbed ion channel mutation. Schweizer et al. (1) reported sarcomere function, DCM by disturbed sarcomere 1 family with a CSRP3 variant that is more in line and cytoskeleton function, and arrhythmogenic right with the causes of myocardial disease, but this was ventricular cardiomyopathy by disturbed desmo- not seen in other gene-positive families. So, how some function (9). For LVNC, the picture is less clear; does LVNC occur? mutations most commonly occur in sarcomere- Neither publication presents mechanistic data, encoding genes, but animal and human data sug- but the investigators speculate on how LVNC and gest a central role of signaling pathways. In the MVP develop. Schweizer et al. (1) noted that HCN4 is cardiomyopathies, ion channel gene mutations also involved in early embryonic heart development, have been implicated, but the causative mecha- helping to form myocardium and the conduction nism(s) remain unclear. system. During later development, HCN4 is down- HCN channels, found in SAN cells and neurons, regulated in the myocardium, with abundant are responsible for hyperpolarization-activated cur- expression restricted to the SAN and conduction rents, called I f in the heart (3,5). The HCN channel system. They hypothesize that HCN4 loss of func- characteristic distinguishing them from other cur- tion interferes with molecular mechanisms required rents is its unique ion selectivity and gating prop- during cardiac development, resulting in LVNC. erties. The HCN channel family has 4 distinct Samsa et al. (11) previously suggested that Notch members, with HCN4 being the prominent cardiac pathway form. Native I f current, as well as the currents whereas sarcomere, cytoskeletal, and Z-disk muta- induced by heterologously expressed HCN channels, tions cause myocardial disease-only phenotypes. disturbance causes CHD, Based on membrane hyperpolarization; 2) channel activation signaling pathway involvement in ventricular wall by direct interaction with cAMP; 3) Naþ and Kþ maturation and compaction (e.g., Notch, Neuregulin, permeability; and 4) a specific pharmacological Ephrin, or Bone morphogenic protein), could be profile. HCN channels consist of 4 subunits arranged involved. Milano et al. (2), on the other hand, sug- around 4 gested that because primary channelopathies are different homotetramers with distinct biophysical associated with myocardial structural abnormalities properties. Each channel subunit consists of: 1) such as DCM, this also occurs with HCN4. Their centrally located, pore-forming et al. with have 4 hallmark properties: 1) channel activation by the this, Schweizer LVNC (1) suggested 769 770 Towbin JACC VOL. 64, NO. 8, 2014 HCN4 and Ventricular Noncompaction AUGUST 26, 2014:768–71 second hypothesis was that LVNC is an acquired is disturbance of signaling pathways leading to an adaptive remodeling feature in response to sinus overlapping phenotype. Notch signaling promotes bradycardia. expression of conduction system-specific genes in One feature of the final common pathway hy- neonatal cardiomyocytes, reprogramming them into pothesis that may be at play here is the concept of cells with conduction system characteristics (15). secondary disruption of the pathway via binding Human and animal studies suggest the Notch partner abnormalities or other secondary causes. pathway is involved in the development of LVNC Examples exist where a mutation in a non–ion with or without CHD. Kuratomi et al. (16) demon- channel-encoding gene, such as caveolin-3 (Cav3) or strated that HCN4 enhancer function is depen- a-syntrophin 1 (SNTA1), disturbs the function of an dent on myocyte enhancer factor-2 (MEF2) binding ion channel binding partner protein such as the sequences, located in the regulatory region of cardiac sodium channel gene, SCN5A, resulting HCN4. in an SCN5A form of long QT syndrome (LQT3) MEF2 mutant inhibits enhancer activity, decreases (12,13). We termed these non-ion channel proteins HCN4 mRNA expression, and decreases If current as ChIPs or channel interacting proteins. Many amplitude, suggesting MEF2 may play a critical role Overexpression of a dominant-negative similar examples exist. Using this example, we in HCN4 transcription. MEF2 signaling pathway could hypothesize that HCN4 mutations cause the molecules interact with Notch pathway molecules, arrhythmia phenotype and also disturb downstream including Hey2 and Tbx20, which are important in binding (sarcomere, the development of the myocardial compact and Z-disk, cytoskeletal proteins, or signaling path- noncompact layers, and are directly affected in ways). There is a relative paucity of information some forms of LVNC (17). It is possible that the regarding HCN4 binding partners, but they include relationship of mutant HCN4 and MEF2 triggers a Cav3, MiRP1 (encoded by the gene KCNE2 and downstream spiral that disturbs Notch pathway shown to be an auxiliary subunit of the HERG function and results in LVNC with or without MVP, channel), KCR1 (plasma membrane-associated pro- whereas bradycardia occurs as a result of the pri- tein that associates with HERG), SAP97 (membrane- mary HCN4 mutation. partners that cause LVNC associated guanylate kinase scaffold protein), and In any case, these findings are intriguing and cyclic AMP. Several of these binding partners are potentially paradigm-shifting. If the investigators or interesting as potential channel interacting protein- others can determine the pathogenic mechanism(s) like proteins. For instance, mutated Cav3 disrupts responsible for this overlapping phenotype, it would SCN5A function causing LQT3 and arrhythmias (12). enhance our knowledge and enable targeted treat- In ment development, especially because LVNC is some patients with SCN5A disruption, an arrhythmogenic DCM phenotype develops. Cav3, commonly associated with arrhythmias (18). SNTA1, and SCN5A also bind to dystrophin, the protein that causes Duchenne and Becker muscular REPRINT REQUESTS AND CORRESPONDENCE: Dr. dystrophy with DCM or LVNC, as does SAP97 (4,14). Jeffrey A. Towbin, The Heart Institute, Division of Could a mutation in HCN4 disrupt the binding of Pediatric Cardiology, Cincinnati Children’s Hospital Cav3, SNTA1, or SAP97 and dystrophin, and be the Medical Center, 3333 Burnet Avenue, Cincinnati, cause of LVNC in these patients? Another possibility Ohio 45229. E-mail: [email protected]. REFERENCES 1. Schweizer PA, Schröter J, Greiner S, et al. The symptom complex of familial sinus node dysfunction and myocardial noncompaction is 4. Towbin JA. Left ventricular noncompaction: a new form of heart failure. Heart Fail Clin 2010;6: 453–69. cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin. Mol Genet Metab 2006;88:78–85. associated with mutations in the HCN4 channel. J Am Coll Cardiol 2014;64:757–67. 5. Biel M, Wahl-Schott C, Michalakis S, Zong X. 8. Bowles NE, Bowles KR, Towbin JA. The “final common pathway” hypothesis and inherited cardiovascular disease: the role of cytoskeletal proteins in dilated cardiomyopathy. Herz 2000; 2. Milano A, Vermeer AMC, Lodder EM, et al. HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy. J Am Coll Cardiol 2014;64: 745–56. Hyperpolarization-activated cation channels: from genes to function. Physiol Rev 2009;89:847–85. 6. Mohapatra B, Jimenez S, Lin JH, et al. Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis. Mol Genet Metab 25:168–75. 3. Herrmann S, Hofmann F, Stieber J, Ludwig A. 2003;80:207–15. 9. Ackerman MJ, Priori SG, Willems S, et al. HRS/ EHRA expert consensus statement on the state of genetic testing for the channelopathies HCN channels in the heart: lessons from mouse mutants. Br J Pharmacol 2012;166:501–9. 7. Bos JM, Poley RN, Ny M, et al. Genotypephenotype relationships involving hypertrophic and cardiomyopathies. Heart Rhythm 2011;8: 1308–39. Towbin JACC VOL. 64, NO. 8, 2014 HCN4 and Ventricular Noncompaction AUGUST 26, 2014:768–71 10. Schulze-Bahr E, Neu A, Friederich P, et al. Pacemaker channel dysfunction in a patient with sinus node disease. J Clin Invest 2003;111:1537–45. syndrome. Circ Arrhythm Electrophysiol 2009;1: 193–201. transcriptional target of MEF2. Cardiovasc Res 2009;83:682–7. 11. Samsa LA, Yang B, Liu J. Embryonic cardiac chamber maturation: trabeculation, conduction, and cardiomyocyte proliferation. Am J Med Genet C Semin Med Genet 2013;163C:157–68. 14. Petitprez S, Zmoos AF, Ogrodnik J, et al. SAP97 and dystrophin macromolecular complexes determine two pools of cardiac sodium channels Nav1.5 in cardiomyocytes. Circ Res 2011;108: 294–304. 17. Luxán G, Casanova JC, Martínez-Poveda B, et al. Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy. Nat Med 2013;19:193–201. 12. Vatta M, Ackerman MJ, Ye B, et al. Caveolin-3 mutations in congenital long QT syndrome: a novel pathogenetic mechanism. Circulation 2006; 114:2104–12. 15. Rentschler S, Yen AH, Lu J, et al. Myocardial notch signaling reprograms cardiomyocytes to a conduction-like phenotype. Circulation 2012;126: 1058–66. Mortality and sudden death in pediatric left ventricular noncompaction in a tertiary referral center. Circulation 2013;127:2202–8. 13. Wu G, Ai T, Kim JJ, et al. A novel alpha-1-syntrophin mutation may cause long QT 16. Kuratomi S, Ohmori Y, Ito M, et al. The cardiac pacemaker-specific channel Hcn4 is a direct KEY WORDS HCN4, ion channels, left ventricular noncompaction, LVNC 18. Brescia ST, Rossano JW, Jefferies JL, et al. 771