Download Ion Channel Dysfunction Associated With Arrhythmia

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