EDITORIAL COMMENT
Lamin A/C Gene and the Heart
How Genetics May Impact Clinical Care*
Luisa Mestroni, MD, FACC, FESC,
Matthew R. G. Taylor, MD, P
H
D
Denver and Aurora, Colorado
Lamins are type V intermediate filament proteins that,
thanks to their tridimensional structure, are able to poly-
merize, forming an organized meshwork. The lamin poly-
mers lie between the inner nuclear membrane and the
chromatin and have a complex role in maintaining nuclear
shape and structure, transcriptional regulation, nuclear pore
positioning and function, and heterochromatin organization
(1). The lamin A/C gene (LMNA) produces two principal
isoforms by alternative splicing, lamin A and C, which are
expressed in a variety of terminally differentiated tissues;
therefore, LMNA mutations can cause multiple seemingly
disparate diseases including dilated cardiomyopathies
(DCM) with conduction disease (CMD1A), the premature
aging syndrome Hutchinson’s progeria, skeletal myopathies
(Emery-Dreifuss and limb-girdle muscular dystrophies),
Charcot-Marie-Tooth type 2B1, familial partial lipodystro-
phy, restrictive dermopathy, and mandibuloacral dyspla-
sia, along with various overlapping phenotypes and rare
variants (1,2).
See page 1250
The causative mechanisms for each phenotype remain the
subject of ongoing studies and debates, but the most
important hypotheses are the nuclear fragility and disrup-
tion of the nuclear architecture, altered nuclear signaling,
and finally, interference with the pre-lamin A processing
leading to nuclear accumulation of pre-lamin A (2).
Cardiolaminopathy. Lamin A/C gene-related DCM is
characterized by progressive heart failure, conduction dis-
ease, absent or variable skeletal muscle involvement, high
mortality rate, and high incidence of sudden death (3,4).
Analysis of the frequency of LMNA mutations in DCM
populations has been quite reproducible in several reports,
accounting for 6% to 8% of DCM up to 9% in explanted
hearts (3,5,6). The frequency reaches 30% in DCM with
conduction disease, particularly when skeletal muscle in-
volvement is present (7,8). In considering the clinical
relevance of the molecular genetics of LMNA, it is impor-
tant to evaluate its impact on prognosis and mortality (9). In
this regard, LMNA is not only the most frequent genes
found in DCM, but also it has been shown to be associated
with a very poor prognosis and high mortality rate.
In this issue of the Journal, Pasotti et al. (10) provide
further insight into the LMNA–DCM phenotype in a
thoughtful study analyzing the long-term outcome of 94
LMNA mutation carriers belonging to 27 different DCM
families. Of these subjects, 60 showed an affected pheno-
type, whereas 34 were clinically unaffected or showed only
minor cardiac abnormalities. During a median follow-up of
nearly 5 years, more than 70% of the affected subjects had an
adverse event. This adverse event was either progressive
intractable heart failure causing death or need of transplant
in one-third of cases, whereas in as many as two-thirds, the
event was a life-threatening arrhythmia. Although this study
may be limited by the retrospective analysis, it remains signif-
icant for several reasons. First of all, the follow-up was
remarkably long, ranging from 3 to 9 years, and subjects were
regularly followed up clinically by the investigators. Second, the
results of this investigation emphasize once more the severe
clinical implications of LMNA mutations in DCM, and
particularly the high incidence of arrhythmia and sudden
death. Interestingly, the investigators found a suggested link to
prior vigorous exercise and the risk of clinical events.
Similar findings were previously reported by other inves-
tigators (3,4,5,11,12). Bécane et al. (11) first reported the
high mortality and morbidity of LMNA in a large French
kindred, in which almost 50% of affected relatives died
suddenly, whereas left ventricular dysfunction was seen to
rapidly progress toward heart failure and heart transplant.
Our group found significant mortality and morbidity among
LMNA carriers compared with other DCM patients in a
cohort of 49 nuclear families (40 with familial DCM and 9
with sporadic DCM) that included 269 subjects, of whom
105 were affected. In this study, there was significant
phenotypic variability, but the presence of skeletal muscle
involvement, supraventricular arrhythmia, and conduction
defects were predictors of LMNA mutations. Furthermore,
LMNA mutation carriers had a significantly poorer survival
compared with noncarrier DCM patients, with an event-
free survival at the age of 45 years of 31% versus 75% for
noncarriers (3). Van Berlo et al. (12) pooled clinical data of
all published carriers of LMNA mutations as a cause of
skeletal and/or cardiac muscle disease. They found that
cardiac dysrhythmias and heart failure were common and
that sudden death was the most frequently reported mode of
death (46%) associated with both the cardiac and the
neuromuscular phenotype. More recently, Meune et al. (4)
*Editorials published in the Journal of the American College of Cardiology reflect the
views of the authors and do not necessarily represent the views of JACC or the
American College of Cardiology.
From the University of Colorado Cardiovascular Institute and Adult Medical
Genetics Program, University of Colorado at Denver and Health Sciences Center,
Aurora, Colorado. Supported by the National Institutes of Health (HL67915-01A1,
HL69071-01, MO1 RR00051-1575), American Heart Association 0150453N, and
Muscular Dystrophy Association PN0007-056.
Journal of the American College of Cardiology Vol. 52, No. 15, 2008
© 2008 by the American College of Cardiology Foundation ISSN 0735-1097/08/$34.00
Published by Elsevier Inc. doi:10.1016/j.jacc.2008.07.021