When Lamins Go Bad:
Nuclear Structure and Disease
Katherine H. Schreiber1and Brian K. Kennedy1,2,*
1Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA
2Aging Research Institute, Guangdong Medical College, Dongguan 523808, Guangdong, China
phenotypically diverse genetic disorders known as laminopathies, which have symptoms that
range from muscular dystrophy to neuropathy to premature aging syndromes. Although precise
disease mechanisms remain unclear, there has been substantial progress in our understanding
of not only laminopathies, but also the biological roles of nuclear structure. Nuclear envelope
dysfunction is associated with altered nuclear activity, impaired structural dynamics, and aberrant
cell signaling. Building on these findings, small molecules are being discovered that may become
effective therapeutic agents.
Since their discovery more than 35 years ago as constituents of
the nuclear lamina (Gerace et al., 1978), the nuclear lamins have
been the subject of intense speculation regarding their possible
roles in almost everything that happens in the nucleus. Early
studies focused on biochemistry and cell biology, with the goal
of achieving a basic understanding of the principles governing
nuclear organization. The nuclear envelope entered the medical
realm in the mid-1990s, when mutations in emerin were identi-
fied in patients with Emery-Dreifuss muscular dystrophy
(EDMD) (Bione et al., 1994). The LMNA gene, encoding all
A-type nuclear lamins, was linked to EDMD a few years later
(Bonne et al., 1999), and links between nuclear structure and
human disease have been studied extensively since then in
labs throughout the world.
With around 15 diseases, including a range of dystrophic and
progeroid syndromes, attributed to LMNA mutations and muta-
tions in genes encoding associated nuclear envelope proteins
imental approaches have evolved. Why do alterations in nuclear
envelope proteins confer disease? What are the mechanisms
underlying disease pathology? Do A-type lamins have a role in
normal aging? Can effective therapies be developed for these
debilitating diseases? Though a range of exciting discoveries
have been made in the last decade, many unknowns remain.
Here, we seek to frame the current questions, propose possible
paths toward mechanistic understanding, and briefly evaluate
the therapeutic possibilities that are starting to emerge. Given
the amount of interest and momentum in the lamin field, it is
feasible that therapies to rescue the pathogenic consequences
of misbehaved nuclear structural components will be developed
in the not-too-distant future.
The nuclear envelope is comprised of two membranes: the
outer nuclear membrane, which is continuous with the endo-
plasmic reticulum, and the inner nuclear membrane, which
associates with the nuclear lamina. Nuclear pore complexes
perforate the nuclear envelope to allow transport between the
cytoplasm and nucleus. The nuclear lamina is primarily
composed of nuclear lamins, which were originally identified
as lamins A, B, and C (Gerace et al., 1978). These proteins
constitute the only class of intermediate filament proteins in
the nucleus and form associated filamentous structures that
underlie the nuclear envelope and interact with neighboring
proteins (Gerace and Huber, 2012). Lamins A and C, as well
as two other variants (C2 and AD10), are classed as A-type
lamins and are encoded by the LMNA gene through alternative
splicing. Three different lamin B family members (B-type
lamins) are encoded by two genes (lamin B1 by LMNB1 and
lamins B2 and B3 by LMNB2).
A- and B-type lamins have fundamentally different properties,
perhaps most importantly by virtue of their different isoelectric
points, which dictate that B-type lamins stay associated with
the nuclear envelope during mitosis while A-type lamins become
soluble. Expression patterns differ as well, with B-type lamins
expressed in most or all cell types and A-type lamins expressed
during cell differentiation in many different developmental
lineages (Ro ¨ber et al., 1989). At the cellular level, both classes
of proteins have been ascribed structural roles in the nucleus
as well as a range of other activities, including coordination of
transcription and replication. While specific functions of A-type
lamins remain somewhat elusive, a number of recentdiscoveries
point to key interactions between lamins and cell proliferation,
differentiation, and stress response pathways.
Both A- and B-type lamins undergo posttranslational pro-
cessing based on a C-terminal CaaX motif that dictates a series
of modifications (Weber et al., 1989); only lamin C avoids this by
virtue of alternative splicing of the LMNA transcript that lacks the
C terminus. As a first step, the cysteine residue is farnesylated.
Next, proteolytic processing leads to cleavage after the cysteine
residue, followed by a carboxymethylation of the new C-terminal
Cell 152, March 14, 2013 ª2013 Elsevier Inc. 1365
residue. Many membrane-associated proteins, including Ras,
undergo this processing event. However, in the case of lamin
A, isoprenylation is a transient event, as a second proteolytic
event mediated by the zinc metalloproteinase Zmpste24 leads
to excision of another 15 amino acids. Due to this cleavage,
mature lamin A lacks the modified cysteine. This process is
clearly important to pathologic states, as laminopathies are
linked to altered processing of lamin A, as well as loss-of-func-
tion mutations in ZMPSTE24.
The reasons for farnesylation of lamin A remain to be eluci-
dated despite extensive efforts. Until recently, the thinking has
been that the transient farnesylation event was needed, through
association of the hydrophobic farnesyl group with the nuclear
envelope, to provide initial recruitment of lamin A to the nuclear
periphery (Hennekes and Nigg, 1994). After assembly into fila-
ments, farnesylation of lamin A may no longer be required.
Consistent with this hypothesis, the nucleus has been shown
to be the site of both lamin A carboxymethylation and proteolytic
cleavage by ZMPSTE24. However, several recent studies using
mice and/or cells engineered to express mutant forms of lamin A
indicate that farnesylation is not required for recruitment (Davies
et al., 2011). For instance, when only a nonfarnesylated version
of lamin A is expressed, normal localization of the lamin A variant
to the nuclear periphery was observed (Davies et al., 2010; Lee
et al., 2010), although mice generated in this manner develop
cardiomyopathy (see below). In addition, mice expressing only
lamin C (not farnesylated) or a mature (preprocessed) lamin A
are (surprisingly) normal and have apparently correct localization
of the respective protein to the nuclear periphery. Though these
in filament assembly or envelope association, they raise serious
questions about the importance of these events in the mouse
and provide an interesting puzzle to be pieced together by future
Diseases Linked to Mutations in Nuclear Structure
The number of different diseases linked to mutationsin LMNA,at
least 15 by now, surpasses that of any other human gene. It is
hard to establish absolute numbers because many of the
associated syndromes have overlapping pathologies. Neverthe-
less, the range of tissues and functions that can be adversely
affected by mutation in LMNA is striking (Table 1). Diseases
include the aforementioned Emery-Dreifuss muscular dystrophy
(EDMD2/3) (Bonne et al., 1999) and a second muscular
dystrophy (Limb-girdle, LGMD1B) (Muchir et al., 2000) that
of muscular dystrophy also present with dilated cardiomyop-
athy, which is often the cause of mortality. Other LMNA muta-
tions lead to dilated cardiomyopathy (CDM1A) without skeletal
muscle involvement (Fatkin et al., 1999). Finally, a form of
congenital muscular dystrophy has more recently been linked
to mutations in LMNA (Quijano-Roy et al., 2008), as well as
Heart-hand syndrome, which couples a range of cardiac defects
to brachydactyly (Renou et al., 2008).
Pathologyassociatedwith LMNAmutationsisnotrestricted to
striated muscle tissue, as other diseases confer loss of adipose
tissue, including Dunnigan-type familial partial lipodystrophy
(FPLD2) (Shackleton et al., 2000), Mandibuloacral dysplasia
(MAD) (Novelli et al., 2002), generalized lipoatrophy (Caux
et al., 2003), restrictive dermopathy (RD) (Navarro et al., 2004),
and other overlapping disorders. Highlighting the importance
of lamin A processing, mutations resulting in loss of ZMPSTE24
function, which result in partially processed lamin A, lead to both
MAD and RD (Agarwal et al., 2003; Navarro et al., 2005).
However, links between lamin A processing and pathology
extend beyond mutations in ZMPSTE24 and connect with
another set of disorders termed progeroid, which give rise to
the appearance of premature aging. The most noted of these
is Hutchinson-Gilford progeria syndrome (HGPS), a severe
disorder for which symptoms, including cachexia, alopecia,
and atherosclerosis, become apparent shortly after birth. Death
results from heart attack or stroke usually before the patient
reaches the age of 20. The most common LMNA mutation
leading to HGPS, G608G, does not affect coding sequence but
instead creates a cryptic splice site leading to removal of
Table 1. Diseases Caused by Mutations in Genes Encoding
Lamins and Lamin-Associated Proteins
Striated Muscle Diseases
Emery-Dreifuss muscular dystrophyLMNA, EDMD, SYNE1,
SYNE2, TMEM43, TMPO
Limb-girdle muscular dystrophyLMNA
Dilated cardiomyopathyLMNA, EDMD, SYNE1,
SYNE2, TMEM43, TMPO
Congenital muscular dystrophyLMNA
Dunnigan-type familial partial
Mandibuloacral dysplasiaLMNA, ZMPSTE24
Accelerated Aging Disorders
Atypical Werner syndrome LMNA
Hutchinson-Gilford progeria syndromeLMNA
Restrictive dermopathyLMNA, ZMPSTE24
Atypical progeria syndrome BANF1
Peripheral Nerve Disorders
Spinocerebellar ataxia type 8SYNE1
Buschke-Ollendorff syndrome LEMD3
Greenberg skeletal dysplasia LBR
1366 Cell 152, March 14, 2013 ª2013 Elsevier Inc.
50 amino acids in the C terminus of lamin A (De Sandre-
named progerin. A similar splicing mutant has been identified
that leads to removal of an extra 40 amino acids (90 total) in
a patient diagnosed with RD (Navarro et al., 2004), leading to
speculation that RD is a more severe version of HGPS, though
the two diseases do not overlap entirely. This splicing event re-
moves the cleavage site for ZMPSTE24, creating a permanently
farnesylated protein that likely causes a dominant gain-of-func-
tion toxicity. Other mutations in LMNA that do not obviously
less severe progeroid pathologies (Cao and Hegele, 2003; Chen
et al., 2003; Verstraeten et al., 2006). Finally, with regard to
LMNA mutations, homozygous loss of lamin A function leads
to Charcot-Marie-Tooth syndrome, characterized by loss of
peripheral nerve myelination (De Sandre-Giovannoli et al., 2002).
Before leaving A-type lamins, it is worth noting the interesting
connections that have arisen with cancer progression (Butin-
Israeli et al., 2012). Most laminopathies are not associated with
cancer, but an increasing range of tumors are characterized by
downregulation of A-type lamin expression (Broers et al., 1993;
Kaufmann, 1992), though results differ in tumor types. Recalling
that this family of lamins is expressed in differentiated cells, but
not stem cells, speculation has developed that A-type lamins
may act as tumor suppressors, perhaps by blocking dedifferen-
tiation into a more stem-cell-like state. A-type lamins have also
been ascribed roles in regulating cell proliferation and the DNA
damage response, either of which could be linked to cancer
progression (Redwood et al., 2011). Among these activities,
A-type lamins are required to stabilize the retinoblastoma tumor
suppressor protein (Johnson et al., 2004). This may be relevant
because the one tumor described in HGPS patients (the sample
size is quite small) is an early onset osteosarcoma (Shalev et al.,
2007), one of the most common tumors linked to homozygous
mutation of the Rb locus (Friend et al., 1986). Although progerin
can stabilize pRb levels (Nitta et al.,2006),the HGPS patient with
osteosarcoma had a rare T623S LMNA mutation that has not
been tested with regard to pRb stability (Shalev et al., 2007).
Mutations in genes encoding other nuclear envelope proteins
are also associated with disease (described in greater detail
in Me ´ndez-Lo ´pez and Worman, 2012). In addition to emerin
and LMNA, mutations in SYNE1 and SYNE2 (encoding
nesprin-1 and nesprin-2), TMEM43 (encoding LUMA), and
TMPO (encoding LAP2-a) are all associated with dilated cardio-
myopathy and muscular dystrophy (Liang et al., 2011; Taylor
et al., 2005; Zhang et al., 2007). These genes encode proteins
that all interact as part of the linker of nucleoskeleton and cyto-
skeleton (LINC) complex, suggesting that altered LINC function
may underlie striated muscle pathology (Puckelwartz and
McNally, 2011). Unrelated SYNE1 and SYNE2 mutations are
also linked to autosomal-recessive spinocerebellar ataxia type
8 and autosomal recessive arthrogryposis, respectively (Attali
et al., 2009; Gros-Louis et al., 2007). LEMD3, encoding MAN1,
an LEM-domain-containing protein, is also associated with
with increased bone density (Hellemans et al., 2004). In addition,
mutations in BANF1, encoding the nuclear envelope protein BAF
that binds DNA and is involved in chromatin organization and
nuclear envelope assembly, are associated with Atypical proge-
ria (Puente et al., 2011).
Not to be left out, LMNB1 and LMNB2 mutations are both
linked to rare diseases. Autosomal-dominant mutations in
LMNB1 lead to adult-onset leukodystrophy, which is character-
ized by central nervous system demyelination (Padiath et al.,
2006). In the case of LMNB2, individuals with heterozygous
mutations are susceptible to acquired partial lipodystrophy,
likely triggered by one of several autoimmune diseases (Hegele
et al., 2006). Finally, the lamin B receptor (LBR), which interacts
with B-typelaminsand mayserveto helplinkthemtothenuclear
envelope and chromatin, is also a target for mutation in two
syndromes: homozygous mutations in LBR cause Greenberg
skeletal dysplasia (Waterham et al., 2003), whereas heterozy-
gous mutations are associated with Pelger-Huet anomaly,
a benign condition characterized by altered chromatin organiza-
tion in granulocytes (Best et al., 2003; Hoffmann et al., 2002).
Given the rate of new discoveries of disease association with
nuclear structural factors, it is fair to speculate that new associ-
ations between disease and nuclear proteins will continue to
Disease Mechanisms: Mouse Models Lead the Way
How could altered function of nuclear structural components
leadto suchawiderangeofdiseases?Adecadeorso ago,there
were few connections between lamins and known disease
mechanisms; however, lamins were known to be important for
a wide range of nuclear functions, including replication and tran-
scription. Many of the initial ideas were based on changes
observed at the level of cell biology. For instance, the shape of
the nucleus was found to be disrupted in fibroblasts lacking
A-type lamins, with enhanced nuclear deformation and sensi-
tivity to mechanical stress (Lammerding et al., 2004). Emerin-
deficit cells have similar properties, and reduced mechanical
stress could explain part of the pathology associated with dis-
eases such as dilated cardiomyopathy and muscular dystrophy,
where affected tissues are under regular strain (Lammerding
et al., 2005). However, cells isolated from human and mouse
tissue from the various laminopathies, all display abnormal
nuclear structure. These phenotypes range from abnormal
nuclear shape to nuclear blebbing and even dispersal of DNA
into the cytoplasm. While these observations may relate to
disease, they do not clearly differentiate one laminopathy from
another, and researchers have turned to more detailed assess-
ments of cellular function to generate more recent hypotheses.
Theories to explain the pathology associated with nuclear
structure defects have emerged largely from two areas: an
extensive set of mouse models and, more recently, studies of
stem cells expressing a range of mutant forms of A-type lamins.
An informative starting point for the former was the generation of
mice lacking A-type lamins (Sullivan et al., 1999). In addition to
being cachexic, these mice present with a subset of the pathol-
ogies associated with LMNA mutation, including muscular
dystrophy, dilated cardiomyopathy, and Charcot-Marie-Tooth
syndrome and succumb to the cardiac phenotype at about
6 weeks of age. Lmna+/?heterozygous mice also develop the
cardiac pathology, although at a slower rate, and mice express-
ing two different LMNA alleles associated with striated muscle
Cell 152, March 14, 2013 ª2013 Elsevier Inc. 1367
disease recapitulate at least some of the human phenotypes
from these findings is that the muscle and peripheral myelination
diseases result from reduced A-type lamin function. This is not
surprising for Charcot-Marie-Tooth syndrome, which is a reces-
sive disorder in humans (De Sandre-Giovannoli et al., 2002).
However, both dominant and recessive mutations have been
identified in the muscle pathologies, and one possibility is that
autosomal-dominant alleles have a dominant-negative effect,
interfering with intermediate filament assembly or some other
property of A-type lamins. Haploinsufficiency also likely explains
the onset of disease in many cases.
It should be noted that the Lmna?/?mouse described origi-
nally may in fact not be a null allele of the gene (Sullivan et al.,
1999). Recent evidence suggests that this mouse expresses
a still incompletely characterized, truncated 54 kDa protein
derived from a splicing event that bypasses the removed exons
(Jahn et al., 2012). While the dust has not settled from this
finding, most data suggest that the lamin A variant expressed
in this mouse is hypomorphic. Interestingly, another Lmna?/?
model has been derived through disruption with a reporter
gene, and this mouse presents with defective development of
et al., 2011). This latter mouse is more consistent with a homozy-
gous LMNA nonsense mutation that resulted in the complete
absence of A-type lamins and was associated with the death
of a newborn patient (van Engelen et al., 2005). Clearly, these
findings call for some re-evaluation of studies performed in the
Lmna?/?mouse despite its past and continued value to the field.
homozygously express a nonfarnesylated version of lamin A in
the absence oflamin C(Daviesetal.,2010). Thesemicewere ex-
pected to resemble the phenotype of mice lacking ZMPSTE24
(see below) but instead present with cardiomyopathy. The inves-
tigators sought to determine whether the cardiac pathology was
attributable to gain-of-function toxicity or a reduced hypomor-
phic function of the lamin A variant. To distinguish, they gener-
ated a mouse expressing a nonfarnesylated allele over a null,
finding that this mouse has a more severe phenotype, consistent
with further reduced lamin A function. If the pathology was
a result of toxicity, the heterozygous mouse would have had
a less severe cardiac phenotype. These findings are consistent
with the data that cardiomyopathy derives from reduced lamin
While striated muscle pathology represents one cluster of
mouse LMNA models, progeria characterizes the other. In this
A variants with processing defects show dominant onset of
a subset of features associated with HGPS. These models are
covered in greater detail in a recent review (Zhang et al., 2013).
Recall that the primary human lesion associated with HGPS is
a heterozygous G608Gmutation,whichcreatesa splicingdefect
and leads to permanently farnesylated lamin A. Much debate
centers around which of the many different HGPS models are
the best to develop mechanistic explanations and therapies for
human patients. Most of the models, including Lmna mutants
and Zmpste24?/?, present with a subset of phenotypes that
are characteristic of progeroid mice, including cachexia,
reduced bone density and rib fractures, loss of subcutaneous
fat, kyphosis, alopecia, and premature death. However, a model
generated to express human progerin from a BAC clone does
not exhibit these phenotypes, instead displaying arterial smooth
muscle defects (Varga et al., 2006). While the differences are
unknown, both types of models may have advantages. For
instance, theBACprogerin modelmimicsatherosclerosis, which
by leading to heart attacks and strokes results in mortality in
most patients. Therefore, studies in this mouse explore effects
on what may be the most important pathology in children with
disease. However, the rapid presentation and wider array of
phenotypes in the other mice offer clear advantages as well. Of
note, some of the progeria model mice display cardiac defects
that are more consistent with dilated cardiomyopathy (Davies
et al., 2010; Yang et al., 2011). One point worth considering is
that a LMNA mutation could lead to gain-of-function toxicity
for some phenotypes and loss-of-function for others.
In the next two sections, we focus on the two classes of
LMNA-associated disease about which we understand the
most: striated muscle disease and progeroid disorders. The
exciting progress in these two areas has led to possible thera-
Disease Mechanisms and Possible Therapies for
LMNA-Associated Striated Muscle Diseases
Interesting findings have emerged on several fronts with respect
to LMNA-associated dilated cardiomyopathy with conduction
defects and muscular dystrophies. While these findings do not
yet come together in a neat package, continued studies may
begin to generate such a composite understanding. The fact
that LMNA mutants leading to EDMD2/3 so closely resemble
X-linked EDMD that is caused by Emerin mutations is a critical
consideration for any mechanistic disease model. Unlike
A-type lamins, emerins reside in the inner and outer nuclear
membranes, interacting with lamins in the former case and
with microtubules in the latter. Lamin A/C binding to emerin is
required for its localization to the nuclear envelope (Vaughan
et al., 2001). This raises the possibility that emerins might be
a conduit by which the nuclear lamina communicates with the
cytoskeleton. However, no clear understanding has emerged
as to how and why the lamin A/C-emerin interaction is important
in skeletal and cardiac muscle.
The linker of nucleoskeleton and cytoskeleton (LINC) protein
complex, consisting of SUN1 and -2 as well as Nesprin 1 and
-2, also connects A-type lamins to the cytoskeleton with Sun
proteins directly interacting with lamin A/C at the inner nuclear
membrane and Nesprins in the lumen (Me ´jat and Misteli, 2010).
Nesprins cross the outer nuclear membranes and connect to
the cytoskeleton in the cytoplasm. In addition to linking the
nucleo- and cytoskeleton, LINC complexes have a wide range
of cellular functions, including in cell division, in centrosome-
nucleus association, in nuclear migration, and in positioning.
Disruption of any of these activities could contribute to disease
progression. A recent study has implicated SUN1 in disease
progression, albeit through an unexpected mechanism. In
mice, SUN1 is dramatically overexpressed and
directed to the Golgi, presumably after nuclear occupancy sites
aresaturated (Chen etal., 2012a). RNAi-mediated knockdown of
1368 Cell 152, March 14, 2013 ª2013 Elsevier Inc.
SUN1 rescued nuclear defects in cell culture, and knockout of
SUN1 significantly extended the survival of Lmna?/?mice. While
significant problem associated with reduced A-type lamin func-
tion is SUN1-mediated toxicity in the Golgi.
Another intermediate filament factor, desmin, serves as a link-
ing factor between lamins and many cytoplasmic structures in
striated muscle cells. Desmin mutations can result in desmin-
related myopathies (DRM), which are characterized by cardiac
and skeletal muscle weakness with a highly variability of presen-
filaments and accumulation of desmin-containing protein aggre-
gates. Interestingly, cardiomyoctes from Lmna?/?mice display
disrupted desminnetworks andelevated protein levels (Nikolova
et al., 2004). This may not be the case for skeletal muscle, as
electron micrographs of muscle biopsies from human patients
failed to detect abnormal desmin localization (Frock et al.,
2012; Piercy et al., 2007). The authors of this study also looked
at murine embryonic stem cells transfected with a human
EDMD mutation and differentiated into cardiomyocytes, finding
no defects in desmin localization. These latter findings appear
to differ from the in vivo studies described above and may
suggest that knockout of A-type lamins, as opposed to expres-
sion of an EDMD missense mutation, is required to induce
abnormal desmin localization. Alternatively, the cell culture
model may not recapitulate events regarding desmin.
Myoblasts generated from Lmna?/?mice are reported to have
differentiation defects, suggesting that reduced regenerative
potential of adult stem cells may combine with increased
damage to myofibers from mechanical stress sensitivity to
explain the rapid onset of dystrophic pathology (Frock et al.,
2006). Interestingly, a small percentage of Lmna?/?myoblasts
responds normally to differentiation signals, whereas a majority
fails to induce the differentiation program. The majority of prolif-
erating Lmna?/?myoblasts also display reduced levels of both
MyoD and desmin. Stable transfection of desmin rescues the
differentiation defects of these cells, implying that reduced des-
min levels during the proliferation phase may, in part, be respon-
sible for the inability of cells to respond to differentiation cues.
Stable expression of MyoD also rescues differentiation defects.
With respect to EDMD mutations, MyoD-transformed human
patient fibroblasts were reported to differentiate normally (Piercy
et al., 2007). Again, the differences may be attributable to the
relative severity of the LMNA mutation, or they may have been
suppressed in the latter case due to artificially high MyoD levels
(Frock et al., 2006; Piercy et al., 2007).
In recent years, it has become apparent that Lmna mutations
can lead to altered activation of major signal transduction path-
ways in the cell (Figure 1). While the mechanisms connecting the
nuclear envelope to cell signaling have not been fully elucidated,
the findings are important because (1) altered signaling can be
linked to pathological progression, and (2) in some cases, small
molecules are available as therapeutic options to correct
signaling defects. In cardiac tissue, three different branches of
the MAP-kinase-signaling pathways have been found to be
aberrantly activated in a mouse model homozygously express-
ing the human LMNA H222P mutant associated with dilated
cardiomyopathy (Muchir et al., 2007b, 2012). One of these, the
extracellular signal-regulated kinase 1/2 (ERK1/2) pathway,
was also upregulated in Emerin-deficient mice, while the Jun
N-terminal kinase (JNK) pathway was not elevated and the
p38a pathway remains to be tested (Muchir et al., 2007a).
Elevated ERK1/2 phosphorylation has also been detected in
sion was inhibited by an siRNA approach and in cardiac tissue
from Lmna?/?mice (Frock et al., 2012; Muchir et al., 2009b). In
Lmna?/?hearts, aberrant phosphorylation could be corrected
by restoration of lamin A expression specifically in cardiomyo-
cytes, indicating that the defects are cell autonomous (Frock
et al., 2012). Finally, elevated p38a phosphorylation has been
detected in heart tissue from human dilated cardiomyopathy
patients (Muchir et al., 2012).
A variety of MAP kinase inhibitors have been generated, and
many have been tested in the clinic for other disease indications.
Worman and colleagues have tested several of these in
LmnaH222p/H222pmice, finding that inhibition of each branch of
the Map kinase pathway delays either onset or progression of
cardiac symptoms (Muchir et al., 2009a, 2012; Wu et al.,
2010). Given that some of these inhibitors appear to be relatively
well tolerated in humans, these findings lead to a potential
therapeutic route for dilated cardiomyopathies associated with
LMNA mutation. Potential benefits for muscular dystrophy
have not been assessed.
pathways? While the answer to this question remains to be
determined, ideas have emerged. For instance, MAP kinases
are known to be activated by mechanical stress, and reduced
A-type lamin function is associated with impaired activation
of mechanosensitive genes in cardiomyocytes. A second more
direct model has potentially emerged that involves direct
Figure 1. Signaling Pathways Disrupted by LMNA Mutations
Recent years have seen several discoveries of signal transduction pathways
that are altered in LMNA mutant backgrounds associated with gain-of-
function toxicity (those involved in Progeria), loss-of-function toxicity (i.e.,
hypomorphic), or both. A list of pathways is provided, as described in detail in
Cell 152, March 14, 2013 ª2013 Elsevier Inc. 1369
interaction between ERK1/2 and A-type lamins in the nucleus.
ERK1/2 is reported to interact with lamin A and the retinoblas-
toma protein (pRb) at the nuclear periphery. Stabilization of
pRb by A-type lamins is important to maintain normal cell-cycle
control (Nitta et al., 2006). Upon serum stimulation of quiescent
cells, ERK1/2 phosphorylates c-Fos, releasing it to stimulate
Ap-1 activation, and also dislodges pRb from A-type lamins,
leading to pRb phosphorylation and E2F activation (Gonza ´lez
et al., 2008; Ivorra et al., 2006; Rodrı ´guez et al., 2010). It is
unclear presently how disruption of the ERK1/2-A-type lamin
interaction by LMNA mutation affects ERK1/2 activation, but
this question needs to be investigated.
Equally unclear are the pathways downstream of MAP kinases
thatmediate cardiac pathology. Twopossibilities haveemerged.
The first involves an observation that connexins are mislocalized
in mice expressing a different mutant associated with DCM
(N195K). Here, connexin 43 was found to be mislocalized and
not associated with gap junctions, a finding that could explain
conduction defects associated with altered A-type lamin func-
tion (Mounkes et al., 2005). Expression of another DCM mutant
(E82K) was found to lead to downregulation and mislocalization
of connexin 43 in neonatal myocytes (Sun et al., 2010). Finally,
a recent study has demonstrated mislocalization of connexin
43 in heart cardiomyocytes of Lmna?/?mice (Frock et al.,
2012). Re-expression of lamin A rescued aberrant ERK1/2 phos-
phorylation and restored connexin 43 localization. Given that
connexins areknown substrates of ERK1/2, the possibility exists
that aberrant activity of this pathway disrupts normal connexin
43 localization and interferes with cardiac conduction (Chen
et al., 2012b).
Two recent studies point to the involvement of another major
signal transduction pathway in LMNA-related cardiac and
skeletal muscle disease. In Lmna?/?mice, the mTORC1
pathway was found to be upregulated in cardiac and skeletal
muscle, leading at least in the heart to impaired autophagy
(Ramos et al.,2012).Reduced mTORC1 signaling bythespecific
kinase inhibitor rapamycin led to enhanced cardiac function and
survival, with indications of improved skeletal muscle function;
the latter possibility needs to be more fully explored. A similar
study conducted in the LmnaH222P/H222Pmouse led to highly
(Choi et al., 2012). Among several upstream activators of
mTORC1 are ERK1/2 MAP kinases, and one possibility is that
increased mTORC1 signaling occurs by this mechanism. How-
ever, there are numerous upstream activators of mTORC1 that
need tobemorefully explored. Thepossibilityof testing rapamy-
cin as a treatment for LMNA-associated DCM is intriguing
because thedrughasbeentested inawiderangeof clinicaltrials
and is approved for multiple disease indications. However, there
are side effects such as dyslipidemia and impaired insulin
signaling that, while generally manageable, must be considered
for treatment of cardiac disease. Elevated mTORC1 signaling,
which is classically associated with increased protein translation
and cell growth, is already linked to forms of cardiac hyper-
trophy. However, general levels of translation do not appear to
be elevated in the Lmna?/?heart (Ramos et al., 2012), suggest-
ing that other pathways are offsetting the translational effects of
mTORC1 in this scenario. Interestingly, rapamycin has been
reported to improve autophagic flux and suppress nuclear
blebbing in fibroblasts expressing progerin, indicating that
suppression of the mTOR pathway may be efficacious in
LMNA-associated progeria models as well (Cao et al., 2011).
Given the remarkable progress in thiscluster of LMNA-associ-
ateddiseases, ithas beenpossible to movefromidentification of
LMNA mutations in EDMD and DCM to possible therapeutic
approaches in less than two decades (Figure 2). Whether the
current drugs will prove efficacious in humans remains to be
seen. Even if this is not the case, new candidate therapeutic
approaches will surely continue to emerge.
Disease Mechanisms and Possible Therapies for
Although very rare, progeria syndromes have long been of great
interest, based in part on the hypothesis that, by learning the
mechanisms underlying their pathology, insights will be made
into the normal aging process. This assumption is yet to be vali-
dated, and researchers in the aging field have a wide range of
viewpoints. One thing is clear. The studies into LMNA-associ-
ated progerias have yielded major biological insights and have
provided hope that therapeutic approaches can be developed
to slow the impact of these very severe syndromes. In this
section, the latest findings in progeria and lamin A processing
will be discussed.
A large body of work suggests that HGPS mutants in LMNA
at least in part confer toxicity by virtue of being permanently
farnesylated. Several deformations of the nucleus were found
in cells expressing progerin or other nonfarnesylated versions
of lamin A, and several studies indicated that these phenotypes
could be rescued by a class of drugs that inhibit farnesyltrans-
ferases (Young et al., 2006). These drugs were initially gener-
ated based on their ability to block Ras farnesylation and the
promise that that would inhibit tumor progression. Though
cancer studies continue, their development has been fortuitous
Figure 2. Potential Therapeutic Approaches to Laminopathies
Several small molecules have been proposed as treatments for laminopathies.
The major ones are listed with arrows indicating the diseases to which they
may have efficacy. Question marks indicate that animal data have yet to be
presented. Notably, FTIs have been tested in human children with HGPS, with
promising initial results (Gordon et al., 2012).
1370 Cell 152, March 14, 2013 ª2013 Elsevier Inc.
to the study of HGPS. Not only do they rescue cellular defects,
but they have beneficial properties when delivered to HGPS
mouse models, extending survival and improving other physio-
logical readouts, including bone and cardiovascular defects
(Capell et al., 2008; Yang et al., 2008b). These findings,
together with the fact that FTIs have good safety profiles in
the clinic, were cause for great optimism, leading to the first
clinical trial in human patients with HGPS. Initial findings were
recently reported showing variable rates of improvement in
vascular function, enhanced bone rigidity, and improved senso-
rineural hearing in 25 patients treated with Ionafarnib for at least
2 years (Gordon et al., 2012).
One reason FTIs may have limited potency is that lamin
A variants can become geranylgeranylated, especially when
farnesyltransferase activity is blocked (Varela et al., 2008). This
pathway upstream in a manner that inhibits both lamin A modifi-
cations might have enhanced efficacy. Consistently, combined
treatment of Zmpste24?/?mice with two such agents, statins
and aminobisphosphonates, enhances survival and improves
several pathologies. Another potential approach has emerged
in a mouse that is genetically engineered to have the exact
G608G mutation (G609G in mice) (Osorio et al., 2011). As in
and progeroid phenotypes. Interestingly, treatment of the mice
with a morpholino-based therapy that prevents pathogenic
splicing delays pathology and extends survival, suggesting an
alternative therapeutic approach.
Genetic studies support the toxicity of farnesylated lamin A in
progerias. For instance, mice lacking Zmpste24 develop pro-
geroid features linked to the toxicity of an unprocessed lamin
A, as deletion of one copy of LMNA in this background improves
the range of phenotypes (Fong et al., 2004). Extensive studies by
Young and colleagues have further elucidated the role of
farnesylation in vivo. Mice engineered to express a nonfarnesy-
lated version of progerin still develop progeroid features, albeit
at a slower rate (Yang et al., 2008a). However, mice expressing
a nonfarnesylated version of prelamin A do not develop proge-
roid features, as described earlier (Davies et al., 2010). One
possible interpretation of these studies in that farnesylation
may be required for toxicity in the case of prelamin A but that
Several lines of evidence implicate enhanced DNA damage
and/or an impaired DNA damage response pathway in the
etiology of HGPS. HGPS cells have higher levels of reactive
oxygen species and greater rates of basal DNA damage (Viteri
et al., 2010). These findings are likely connected, as a reduction
in ROS by exposure to n-acetylcysteine reduces double-strand
break formation. These alterations lead, in part, to enhanced
activation of DNA response pathways, including enhanced
ATM and RAD3-associated foci, which may adversely affect
cell-cycle proliferation. An interesting and unusual feature of
HGPS cells is persistent basal levels of phosphorylated gH2AX
foci marking double-strand breaks that also stain positive
for Xeroderma pigmentosum group A protein (XPA) (Liu et al.,
2008), a component of nucleotide excision repair. No other
related factors are upregulated, suggesting that the foci have
an abnormal set of repair proteins and the type of DNA damage
in HGPS cells may have unique features.
Cells from mice lacking Zmpste24 also exhibit a significant
delay in recruitment of 53BP1 to sites of DNA repair after induc-
tion of double-strand breaks (Liu et al., 2005). p53 targets such
as GADD45, p21, and ATF3 were also elevated, and deletion of
p53 was sufficient to rescue some of the progeroid phenotypes
of the Zmpste24?/?mouse (Varela et al., 2005). Though p53
targets were not elevated in HGPS fibroblasts, inactivation of
the transcription factor was sufficient to suppress premature
senescence (Kudlow et al., 2008). More recent data indicate
that ATM and NEMO pathways become activated and promote
NF-kB-dependent inflammation in both Zmpste24?/?
cological interventions of these pathways slow progeroid
pathology and enhance survival. These findings are particularly
interesting because (1) they suggest that NF-kB inhibitors may
be effective therapeutic agents and (2) enhanced inflammation
may be a major driver of normal aging processes. Furthermore,
unresolved. Progeria involves systemic pathology, and one
possibility is that defects in every tissue cause cell autonomous
systemic responses that impact the whole organism. Enhanced
NF-kB signaling could mediate such a systemic effect.
A more straightforward approach to understanding the role of
A-type lamins in DNA damage responses may involve loss-of-
function studies. In contrast to progeroid models, loss of
A-type lamins leads to 53BP1 degradation by the proteasome
(Gonzalez-Suarez et al., 2009). In its absence, repair of double-
strand breaks proceeds more slowly, hindering effective nonho-
mologous end joining (Redwood et al., 2011). Homologous
recombination is also compromised through a transcriptional
mechanism by which enhanced proteasome-dependent degra-
dation of pRb and p107 leads to repression of RAD51 and
BRCA1 (Redwood et al., 2011). It remains unclear why enhanced
protein turnover of pRb and 53BP1 occur in the absence of
A-type lamins, but the hypothesis has been put forward that
A-type lamins may have a general role in promoting the
stability of several nuclear regulatory factors through keeping
proteasome-dependent degradation in check (Parnaik et al.,
2011). It should also be noted that many of these properties
may explain why loss of A-type lamin expression could have
In addition to impaired DNA damage response pathways,
telomere dysregulation may also contribute to progeroid
pathology. In culture, HGPS fibroblasts experience faster telo-
mere shortening, and normal fibroblasts expressing progerin
recapitulate this phenotype and also enhance formation of
signal-free ends (Decker et al., 2009). Enhanced telomere attri-
tion may contribute to proliferation defects and early senes-
cence, as telomerase expression restores both properties in
fibroblasts (Benson et al., 2010; Kudlow et al., 2008). One role
of telomerase may be to enhance resolution of DNA damage
foci, which were found to localize in regions near telomeres
(Bensonetal.,2010).Themechanisms bywhich thismightoccur
and the extent to which altered telomere dynamics promotes
progeroid pathology remains to be determined.
Cell 152, March 14, 2013 ª2013 Elsevier Inc. 1371
Given that HGPS (and other laminopathies) primarily affect
tissues of mesenchymal origin, altered mesenchymal stem cell
function may be a major site of progerin-induced dysfunction.
Gene expression profiling in fibroblasts expressing progerin
to be highly enhanced (Scaffidi and Misteli, 2008). Elevated
Notch activity associated with progerin expression was found
to promote expression of a range of differentiation markers in
human mesenchymal stem cells. As a possible mechanism,
progerin was found to disrupt nuclear matrix association of
SKIP, a coactivator of Notch genes, leading to its release into
the nucleoplasm and activation of targets. Reduced mesen-
chymal stem cell function could promote a subset of progeroid
phenotypes in vivo, but this remains to be tested.
The Wnt/b-catenin pathway is altered in a variety of laminopa-
thies as well. In both Zmpste24?/?and HGPS mice, reduced
b-catenin levels were detected, and cell proliferation defects
could be rescued by inhibition of Gsk-3b, leading to b-catenin
stabilization (Espada et al., 2008; Hernandez et al., 2010). Of
note, the Wnt pathway may be disrupted in mice lacking emerin
(Markiewicz et al., 2006; Tilgner et al., 2009). Given that the Wnt
pathway may have critical roles in maintaining adult stem cell
function with age, the role of this pathway in laminopathies
requires further interrogation.
Adult stem cells may also be impaired in progeroid laminopa-
thies due to impaired SIRT1 function. Arecent study has demon-
strated that A-type lamins interact with the protein deacetylase
and that preprocessed lamin A disrupts this association in
Zmpste24?/?cells, leading to reduced deacetylase activity and
rapid in vivo stem cell depletion (Liu et al., 2012). Treatment of
mice with resveratrol restores SIRT1 activity, reduces the
pathology, and extends survival, indicating that enhancing
disorders associated with LMNA mutation.
Since the identification, in 1999, of diseases caused by muta-
tions in genes encoding for nuclear lamina proteins, research
has been dedicated toward understanding the molecular mech-
anisms leading to these specific phenotypes. Understanding
how the nuclear lamina interacts with structural proteins, chro-
matin, transcription factors, and other signaling partners will
likely give us an understanding of mechanistic links to disease.
At this moment, the puzzle is starting to come together, but the
overall picture of how lamins regulate all of these pathways
and how this regulation leads to disease is still developing.
Understanding the mechanisms by which mutations in lamins
cause these rare diseases will provide molecular insight into
other common conditions that laminopathies model, such as
muscle diseases and cardiomyopathy. Additionally, because
mutations in the nuclear lamina result in rapid aging-like disease,
longevity will be of great importance.
The authors would like to apologize to those scientists whose studies were
not referenced due to space limitations and also acknowledge the editorial
contributions of Juniper Pennypacker. Lamin-related research in the lab of
B.K.K. is supported by a grant from the National Institute of Aging (R01
AG024287). K.H.S. is supported by a Ruth L. Kirschstein NRSA Postdoctoral
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