(Circulation. 2001;103:65.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
-Tropomyosin Mutation (V95A) Is Associated With Mild Cardiac Phenotype, Abnormal Calcium Binding to Troponin, Abnormal Myosin Cycling, and Poor Prognosis
From the Department of Medicine, Baylor College of Medicine (A.K., L.L.B., R.R.), Houston, Tex; Departments of Internal Medicine (L.S.T., J.S., C.B.) and Biochemistry (L.S.T.), University of Iowa, Iowa City, Iowa; Department of Physiology (N.B., E.H.), University of California, Los Angeles; and National Heart, Lung, and Blood Institute (A.E.A., A.O., L.F.), National Institutes of Health, Bethesda, Md.
| Abstract |
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-tropomyosin
(TPM1) mutation and examine the
pathogenesis of the clinical disease by characterizing functional
defects in the purified mutant protein. Methods and ResultsHCM was linked to the TPM1 gene (logarithm of the odds [LOD] score 3.17). Sequencing and restriction digestion analysis demonstrated a TPM1 mutation V95A that cosegregated with HCM. The mutation has been associated with 13 deaths in 26 affected members (11 sudden deaths and 2 related to heart failure), with a cumulative survival rate of 73±10% at the age of 40 years. Left ventricular wall thickness (mean 16±6 mm) and disease penetrance (53%) were similar to those for the ß-myosin mutations L908V and G256E previously associated with a benign prognosis. Left ventricular hypertrophy was milder than with the ß-myosin mutation R403Q, but the prognosis was similarly poor. With the use of recombinant tropomyosins, we identified several functional alterations at the protein level. The mutation caused a 40% to 50% increase in calcium affinity in regulated thin filamentmyosin subfragment-1 (S1) MgATPase assays, a 20% decrease in MgATPase rates in the presence of saturating calcium, a 5% decrease in unloaded shortening velocity in in vitro motility assays, and no change in cooperative myosin S1 binding to regulated thin filaments.
ConclusionsIn contrast to other reported TPM1 mutations, V95A-associated HCM exhibits unusual features of mild phenotype but poor prognosis. Both myosin cycling and calcium binding to troponin are abnormal in the presence of the mutant tropomyosin. The genetic diagnosis afforded by this mutation will be valuable in the management of HCM.
Key Words: cardiomyopathy genetics death, sudden prognosis
| Introduction |
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60%), mild cardiac phenotype in young
subjects, and a favorable
prognosis.1 2 3
HCM due to cardiac troponin-T gene
(TNNT2) is usually associated
with relatively low disease penetrance (
80%) and mild LVH but a
high incidence of sudden
death.6
The TPM1 gene
consists of 14 exons and 4 isoforms (
- and ß-tropomyosins,
tropomyosin-4, and
tropomyosin-30).1 8
The cardiac isoform is generated from 10 exons, is expressed in both
myocardium and fast skeletal muscle fibers, and consists of 284 amino
acids.8 Tropomyosin, actin,
and troponin complex (troponins T, C, and I) make up most of the thin
filament in striated muscle. Tropomyosin is a rigid, rodlike protein
that binds along the length of the actin filament and is intimately
associated with troponin
complex.9 It adds to the
rigidity and stability of the thin filament. In the absence of
Ca2+ binding to troponin C,
-tropomyosin
inhibits the binding of myosin to actin. Binding of
Ca2+ to troponin C results in the release of
myosin-binding site of actin by the tropomyosin-troponin
complex. The interaction of actin and myosin heads then generates
contractile
force.9 10
Mutations in TPM1
account for
3% of cases of
HCM.11 12 13 14
Four TPM1 mutations have been
described: A63V, K70T, D175N, and E180G. The first 2 mutations are
located in exon 2b in an area that may alter the binding of
-tropomyosin to actin, and the latter 2 mutations are located in
exon 5 near a Ca2+-dependent troponin-T
binding domain.
We report here a novel TPM1 missense mutation with the unique features of mild cardiac hypertrophy but a high mortality rate. We also describe the properties of the isolated mutant protein, which exhibits fundamental defects in regulatory function.
| Methods |
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Genetic Studies
Linkage analysis was performed with markers from the
ABI screening set 215 and
MLINK module of the LINKAGE 5.2
program.16 Sequences from
exon 1 to exon 9a,b of TPM1
were amplified from genomic DNA with primers as previously
described17 for 2 affected
and 2 control individuals. To confirm segregation of the mutation in
the family and absence of the mutation in normal subjects, amplified
exon 3 fragments were digested with restriction endonuclease
DdeI (Boehringer-Mannheim) and
analyzed by electrophoresis through a 2% agarose
gel.
Clinical Studies
Studies included 2D echocardiography, 12-lead ECG,
and in selected cases, treadmill exercise test, exercise thallium
scintigraphy, MRI, cardiac catheterization, and angiography. We also
reviewed the clinical records, death certificates, and autopsy reports
of 6 family members who died suddenly.
HCM was defined as LV wall thickness >13 mm in the absence of another cause for the LVH. Disease penetrance was defined as number of family members with HCM divided by the number of family members with the mutation.
The findings were compared with those previously reported for the MYH7 mutations L908V, G256E, and R403Q with well-defined clinical characteristics.4 5
Biochemical Studies
Polymerase chain reactionbased mutagenesis of
Ala-Ser rat striated muscle
-tropomyosin18 was
performed as described
previously19 to produce cDNA
encoding the V95A mutation. The fidelity of the entire coding sequence
was confirmed by automated DNA sequencing. As previously for other
recombinant tropomyosins, wild-type and mutant tropomyosins were
expressed in DE3 cells with the pET3d expression
vector20 and then purified
to homogeneity.20 Purified
actin,21 myosin
subfragment-1 (S1),22 and
troponin23 were obtained as
described previously.
Thin filamentmyosin S1 MgATPase rates were determined by release of 32P-Pi from ATP,24 25 and the free calcium concentration was manipulated with mixtures of CaCl2 and di-bromo BAPTA.26 MgATPase data as a function of the free calcium concentration were analyzed according to equation 12 in Tobacman and Sawyer,26 using Scientist for nonlinear least squares fitting. We determined in vitro motility by labeling reconstituted regulated thin filaments with rhodamine-phalloidin and monitoring their movement over a rabbit skeletal heavy meromyosincoated surface using epifluorescence microscopy and quantitative analysis of motion.27 28 Actin-myosin S1 binding was monitored by steady-state fluorescence with pyrene-labeled actin as described by Criddle et al29 and Rosol et al.30 These data were analyzed according to the model of Hill et al31 for cooperative myosin binding to the thin filament, using Scientist for nonlinear least squares curve fitting.
Statistics
Patient data are presented as mean±SD. Differences
for mean values of maximum LV wall thickness were compared by
Students t test. Cumulative
survival was determined by product-limit survival analysis with sudden
death as the time variable. The log-rank test was used to compare
actuarial survival curves. A 2-tailed value of
P<0.05 was considered
significant.
| Results |
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Cardiac Phenotype
The data of 26 affected family members were examined.
The individuals included all 14 members positive for the mutation, 11
additional members who died of the disease, and an affected family
member for whom no DNA was available. The area of maximum LV wall
thickness was localized to posterior basal wall, anterolateral free
wall, and/or apex in 9 patients. None of the patients had LV outflow
obstruction.
Maximum LV wall thickness was 16±6 mm (range 8 to 27 mm). MRI-aided diagnosis of HCM as LVH was very localized in some patients.
The ECG was abnormal in 11 (79%) of 14 affected family members, but only 6 (43%) showed LVH by voltage criteria. Eight (57%) of the 14 affected members showed ST-Twave abnormalities. Two subjects with LV wall thickness of 10 and 13 mm, respectively, developed significant ST-wave depression during treadmill test but had normal coronary angiograms.
Disease Penetrance
Figure 3
shows the relation between maximum LV wall
thickness and age in the family members. The maximum LV wall thickness
was <12 mm in all adult members without the mutation. LVH and disease
penetrance (53%, 8 of a total of 15 affected members in whom
echocardiograms were available) were similar to subjects with the
MYH7 mutations G256E and L908V
(Figure 4
). LVH and penetrance were significantly less than
in the MYH7 mutation
R403Q.
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Prognosis
LV systolic dysfunction was noted in 5 patients; 3 were
complicated by symptomatic bradycardia or cardiac arrest, and 2 are
asymptomatic. There have been 13 deaths: 11 sudden deaths and 2 related
to heart failure. Four of the sudden deaths were related to physical
activity; 2 occurred in subjects with mild or no LVH. An additional
patient has presyncope with exertion. Cumulative survival rates have
been 73±10% and 32±13% at 40 and 60 years of age, respectively. The
survival rate was worse than that for the
MYH7 mutations L908V and G256E
and similar to that for the
MYH7 mutation R403Q
(Figure 5
).
|
Effect of the Mutation on Protein
Function
Effect of the Mutation on Calcium-Sensitive
Regulation of Acto-Myosin S1
To understand how the mutation acts to produce the
observed clinical phenotype, control and mutant tropomyosins were
expressed in bacteria and their properties studied in detail. Previous
studies of HCM tropomyosin mutants 175 and 180 suggested that these
alterations increased the calcium sensitivity of muscle contraction in
fibers or cells containing mixtures of normal and mutant
molecules.32 33
This effect has not been demonstrated in a purified reconstituted
system for any HCM tropomyosin mutation. Thin filaments were
reconstituted with actin, troponin, and recombinant tropomyosin, and a
biochemical correlate of muscle regulation was evaluated:
calcium-sensitive regulation of myosin S1 MgATPase activity.
Representative data are shown in
Figure 6
. The V95A mutation resulted in abnormal regulation,
characterized most notably by increased calcium affinity. To examine
this more precisely, multiple experiments performed as in
Figure 6
showed a 40% to 50% increase in apparent calcium
affinity, from 3.2±0.5 to 5.0±0.7x105
M-1, a 0.2 pCa shift. Also,
Figure 6
suggests and additional determinations confirmed
that the maximum MgATPase rate in the presence of saturating calcium
was diminished from 2.95±0.20 to 2.28±0.18
s-1, a 22±6% decrease in paired studies
(n=5). This small but reproducible effect implies an effect of the
mutation on myosin cycling. There were no statistically significant
effects on the cooperativity of activation (Y=13±4 for control and
8±3 for V95A where
Y
nH19 26 )
or on the ATPase rate in the absence of calcium (0.24±0.05 versus
0.25±0.02 s-1)
(Figure 7
).
|
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Effect on In Vitro Motility
To determine whether the mutation altered mechanical
actin-myosin function, the in vitro motility of control and mutant
filaments was examined. Wild-type or mutant tropomyosin-containing
actin-troponin-tropomyosin filaments were combined with
rhodamine-phalloidin, and their unloaded sliding over a heavy
meromyosincoated surface was
measured.27 The data were
analyzed 2 ways: for all of the observed filaments, and for the subset
of filaments that moved over the surface at a continuous, smooth speed.
In either case, the effect of the mutations was a small decrease (5%)
in the maximum sliding speed in the presence of saturating calcium
(Table
).
The large values of n (range 179 to 232) resulted in low standard
errors for these measurements. (Standard deviation values are shown in
the
Table
).
Both control and mutant filaments were highly regulated by calcium: in
the presence of calcium, 90% of the filaments moved smoothly and
rapidly, whereas in the absence of calcium, <2% moved smoothly and
did so at speeds that were decreased by 90%. These in vitro motility
data are consistent with the MgATPase data; the mutation produces
subtle alterations in myosin cycling but does not prevent
regulation.
|
Effect on Myosin Cross-Bridge Binding to the
Filament
The above effects could in principle be due to altered
myosin binding to thin filaments containing the mutant tropomyosin. To
evaluate this, actin was labeled on Cys374 with
n-(1-pyrenyl)iodoacetamide, and
binding of myosin S1-ADP to thin filaments was monitored by
steady-state fluorescence. Thin filaments containing pyrene actin,
troponin, and either wild-type or mutant tropomyosin were examined in
the presence or absence of calcium. In both cases, tropomyosin had no
effect on the myosin-binding isotherm
(Figures 7A
and 7B
), indicating that the V95A mutation does
not alter myosin binding to the thin
filament.
| Discussion |
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V95A Mutation in
TPM1 and
-Tropomyosin
Function
That the TPM1
mutation V95A causes HCM is supported by several observations. First,
linkage analysis showed a statistically significant linkage of the
disease locus to chromosome 15q22. Second, the mutation was present in
all clinically affected family members but not in 200 normal
individuals (400 chromosomes; population frequency <0.25%). In
addition, the mutated valine residue has been highly conserved in
vertebrates throughout evolution.
In a series of recent articles,18 19 30 a region of tropomyosin that includes the site of the V95A mutation has been implicated as critical for thin filament activation. Preceding structural work34 35 36 suggested that the thin filament has 3 conformations: (1) without Ca2+ bound to troponin, and with tropomyosin blocking the myosin binding site on actin; (2) with Ca2+ bound to the troponin, causing tropomyosin movement on actin to partially expose the binding site for myosin; and (3) a third (fully active) conformation in which myosin is bound and the tropomyosin moves further.37 Tropomyosin residues 89 to 207 appear to be critical for stabilizing this final state of the thin filament, which is required for thin filament activation. The V95A mutation may alter 1 or more transitions among these states.
Similarly, tropomyosin HCM mutations at positions D175N and
E180G have been proposed to alter thin filament
activation,38 39
although neither myosin affinity nor Ca2+
affinity was examined for these mutants. Functional studies of
TPM1 cDNA expressed in skeletal
muscle and those performed on single skinned skeletal fibers from
transgenic animals and affected patients demonstrated increased
Ca2+
sensitivity.32 39 40
Furthermore, adenovirus-mediated expression of several HCM-causing
tropomyosins at the 35% level in adult cardiac myocytes resulted in
Ca2+-sensitizing effects on
force,33 with severity
dependent on the mutation.
Figures 6
and 7
in the present work show a similar effect
under highly defined conditions using purified proteins and demonstrate
that the effect is not due to increased myosin binding. By implication,
it is calcium affinity per se that is altered for this mutation.
Michele et al33 suggested
that the severity of the calcium-sensitizing effect may correlate with
clinical severity. However, the clinical severity of the V95A patients
is particularly high, yet the alteration in
Ca2+ sensitivity for reconstituted 100%
mutant filaments
(Figure 6
) is no greater than that observed for 35% mutant
fibers.33 Altered myosin
cycling
(Figure 6
, the
Table
)
may also be an important contributor to disease
pathogenesis.
Cardiac Phenotype and Prognosis
Clinical characteristics and prognosis associated with
mutations of TPM1 have not been
well characterized owing to small size and composition of affected
families. In previous reports, HCM caused by the
TPM1 mutation D175N showed a
variable phenotype with a good
prognosis.14 The
TPM1 mutation E180G has been
associated with mild LVH, but the prognosis is
unclear.17 Few HCM cases
caused by the TPM1 mutations
A63V and K70T have been reported: mild LVH associated with sudden
death, congestive heart failure, and LV
dilatation.12 13
In the present kindred, the mean maximum LV wall thickness was 16±6 mm
in the 15 affected members. The presence of cardiomyopathy was
indicated by abnormal ECG in several carriers of the mutation in the
absence of LVH. Conversely, ECG criteria cannot be used to diagnose the
V95A mutation, because a number of affected family members did not have
classic ECG features associated with HCM. However, under the age of 50
years, an abnormal ECG often indicated disease in the absence of LVH.
The distribution of LVH was unusual. Although the disease penetrance
was only 53%, overall, clinical features of this
TPM1 mutation V95A, including
LVH, LV dysfunction, and sudden death, were observed in 85% of the
affected members. Although clinical and genetic data were not available
in several of the deceased family members, the history of sudden death
at young ages provided compelling evidence that the events were related
to the disease mutation. Notably, the clinical expression and calcium
sensitivity of TPM1 mutation
V95A are similar to HCM caused by
TNNT2 mutations associated with
similarly poor
prognosis.41
Genotyping is important for definitive diagnosis, because the myopathy is associated with atypical findings. Detection of the TPM1 mutation V95A is important for early counseling and treatment of family members.42
| Acknowledgments |
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| Footnotes |
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Guest Editor for this article was Ketty Schwartz, PhD, Group Hospitalier Pitie-Salpetriere, Paris, France.
Received April 19, 2000; revision received July 26, 2000; accepted August 14, 2000.
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M. J. Heller, M. Nili, E. Homsher, and L. S. Tobacman Cardiomyopathic Tropomyosin Mutations That Increase Thin Filament Ca2+ Sensitivity and Tropomyosin N-domain Flexibility J. Biol. Chem., October 24, 2003; 278(43): 41742 - 41748. [Abstract] [Full Text] [PDF] |
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S. L. Van Driest, E. G. Ellsworth, S. R. Ommen, A. J. Tajik, B. J. Gersh, and M. J. Ackerman Prevalence and Spectrum of Thin Filament Mutations in an Outpatient Referral Population With Hypertrophic Cardiomyopathy * Note Added in Proof Circulation, July 29, 2003; 108(4): 445 - 451. [Abstract] [Full Text] [PDF] |
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J. Kohler, Y. Chen, B. Brenner, A. M. Gordon, T. Kraft, D. A. Martyn, M. Regnier, A. J. Rivera, C.-K. Wang, and P. B. Chase Familial hypertrophic cardiomyopathy mutations in troponin I (K183{Delta}, G203S, K206Q) enhance filament sliding Physiol Genomics, July 7, 2003; 14(2): 117 - 128. [Abstract] [Full Text] [PDF] |
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B. Kaynak, A. von Heydebreck, S. Mebus, D. Seelow, S. Hennig, J. Vogel, H.-P. Sperling, R. Pregla, V. Alexi-Meskishvili, R. Hetzer, et al. Genome-Wide Array Analysis of Normal and Malformed Human Hearts Circulation, May 20, 2003; 107(19): 2467 - 2474. [Abstract] [Full Text] [PDF] |
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R. J. Jongbloed, C. L. Marcelis, P. A. Doevendans, J. M. Schmeitz-Mulkens, W. G. Van Dockum, J. P. Geraedts, and H. J. Smeets Variable clinical manifestation of a novel missense mutation in the alpha-tropomyosin (TPM1) gene in familial hypertrophic cardiomyopathy J. Am. Coll. Cardiol., March 19, 2003; 41(6): 981 - 986. [Abstract] [Full Text] [PDF] |
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A. J. Marian On predictors of sudden cardiac death in hypertrophic cardiomyopathy J. Am. Coll. Cardiol., March 19, 2003; 41(6): 994 - 996. [Full Text] [PDF] |
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A. Hinkle and L. S. Tobacman Folding and Function of the Troponin Tail Domain. EFFECTS OF CARDIOMYOPATHIC TROPONIN T MUTATIONS J. Biol. Chem., January 3, 2003; 278(1): 506 - 513. [Abstract] [Full Text] [PDF] |
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K. Pieples, G. Arteaga, R. J. Solaro, I. Grupp, J. N. Lorenz, G. P. Boivin, G. Jagatheesan, E. Labitzke, P. P. deTombe, J. P. Konhilas, et al. Tropomyosin 3 expression leads to hypercontractility and attenuates myofilament length-dependent Ca2+ activation Am J Physiol Heart Circ Physiol, October 1, 2002; 283(4): H1344 - H1353. [Abstract] [Full Text] [PDF] |
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R. Roberts and U. Sigwart New Concepts in Hypertrophic Cardiomyopathies, Part I Circulation, October 23, 2001; 104(17): 2113 - 2116. [Full Text] [PDF] |
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J. H. Brown, K.-H. Kim, G. Jun, N. J. Greenfield, R. Dominguez, N. Volkmann, S. E. Hitchcock-DeGregori, and C. Cohen Deciphering the design of the tropomyosin molecule PNAS, June 28, 2001; (2001) 131219198. [Abstract] [Full Text] [PDF] |
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J. H. Brown, K.-H. Kim, G. Jun, N. J. Greenfield, R. Dominguez, N. Volkmann, S. E. Hitchcock-DeGregori, and C. Cohen Deciphering the design of the tropomyosin molecule PNAS, July 17, 2001; 98(15): 8496 - 8501. [Abstract] [Full Text] [PDF] |
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