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
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