?The?Journal?of?Clinical?Investigation http://www.jci.org Volume 119 Number 7 July 2009
Laminopathies and the long strange trip
from basic cell biology to therapy
Howard J. Worman,1,2 Loren G. Fong,3 Antoine Muchir,1,2 and Stephen G. Young3,4
1Department of Medicine and 2Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, New York, USA.
3Department of Medicine and 4Department of Human Genetics, UCLA David Geffen School of Medicine, Los Angeles, California, USA.
The nuclear lamina is an intermediate filament (IF) network
composed of proteins called lamins and is part of the nuclear
envelope of all somatic cells. For many years, research on the
nuclear lamina was the domain of a relatively small group of
cell biologists working on nuclear structure and mitosis. In the
past decade, however, interest in the nuclear lamina has exploded
with the discovery that mutations in the genes encoding lamins
and associated nuclear envelope proteins cause a diverse range
of human diseases. The mechanisms by which abnormalities
in the nuclear lamina cause distinct human diseases (known as
laminopathies) involving different tissues and organ systems have
remained obscure. This review provides a general introduction to
the nuclear lamins, focusing on “lacunae” in our understanding
of these proteins. We focus on work in mammals but recognize
that important insights regarding lamins have originated from
studies of a number of other organisms (in particular, Xenopus,
Drosophila, and Caenorhabditis elegans). We also discuss mechanisms
by which mutations in lamin A/C (LMNA), the gene that encodes
lamins A and C, might cause disease as well as potential therapeu-
tic interventions for laminopathies.
The nuclear envelope and nuclear lamina
The nuclear lamina, an IF network. The nuclear envelope, which is
composed of nuclear membranes, nuclear pore complexes, and
the nuclear lamina, separates the nucleus from the cytoplasm.
The nuclear lamina is a meshwork of IF proteins known as lam-
ins and is localized primarily on the inner aspect of the inner
nuclear membrane (1–4) (Figure 1). In vertebrates, lamins have
molecular masses of 60–80 kDa and generally have been divided
into two groups, A type and B type, based on differences in iso-
electric points (5).
We now know that, in humans, three genes encode nuclear
lamins (Figure 1). LMNA on chromosome 1 encodes the A-type
lamins, with lamins A and C being the main isoforms in somatic
cells (6). Lamins A and C are produced by alternative splicing,
and the first 566 amino acids of the two proteins are identi-
cal. Lamin C has 6 unique amino acids at its carboxyl termi-
nus, while prelamin A, the precursor of mature lamin A, has
98 unique amino acids. The B-type lamins lamin B1 and lamin
B2 are encoded by lamin B1 (LMNB1) on chromosome 5 and
lamin B2 (LMNB2) on chromosome 19, respectively (7, 8).
B-type lamins are expressed in all somatic cells, whereas lam-
ins A and C are absent from some undifferentiated cells (9, 10).
Germ cell–specific transcripts of LMNB1 and LMNA occur as a
result of alternative splicing.
Like other IF proteins, lamins have conserved α-helical central
rod domains and variable head and tail domains (Figure 1). The
basic filament building block is a lamin–lamin dimer. Higher-order
polymers are generated from these units, but the precise mecha-
nisms underlying polymer formation are not well understood. It
seems that most mammalian lamins can interact with themselves
or any other lamin. However, some data show that the strength of
binding between different lamins may vary and that A-type and
B-type lamins may preferentially polymerize in distinct homopoly-
mers (11, 12). Lamins differ from cytoplasmic IF proteins in that
they contain an additional 42 amino acids in their rod domains
and have nuclear localization signals in their tail domains.
Lamins not only interact with each other but also with proteins
of the inner nuclear membrane, transcription factors, DNA, and
chromatin (13) (Figure 1). The organized structure of the nuclear
lamina, chromatin, and nuclear envelope in interphase is disrupt-
ed during mitosis, when these structures disassemble, allowing
chromosome segregation to occur. Nuclear lamina depolymer-
ization during mitosis occurs as a result of phosphorylation of
specific amino acids of the lamins (5, 14). Most likely, this is also
responsible for the separation of lamins from inner nuclear–mem-
brane proteins and chromatin. During mitosis, the inner nuclear
membrane loses its definition and its proteins are resorbed into
the ER (15, 16). At the end of mitosis, the nuclear envelope and
lamina reassemble in a stepwise manner, with targeting of inte-
gral inner nuclear–membrane proteins to chromatin likely to
Conflict?of?interest: H.J. Worman and A. Muchir are inventors on an international
patent application filed by the Trustees of Columbia University on MAP kinase inhibi-
tion to treat cardiomyopathy.
Nonstandard?abbreviations?used: EDMD, Emery-Dreifuss muscular dystrophy;
FPLD2, Dunnigan-type familial partial lipodystrophy; FTase, farnesyltransferase; FTI,
FTase inhibitor; GGTase-I, geranylgeranyltransferase-I; HDJ-2, human DnaJ homo-
log-2; HGPS, Hutchinson-Gilford progeria syndrome; IF, intermediate filament; RD,
restrictive dermopathy; ZMPSTE24, zinc metallopeptidase, STE24 homolog.
Citation?for?this?article: J. Clin. Invest. 119:1825–1836 (2009). doi:10.1172/JCI37679.
1826? The?Journal?of?Clinical?Investigation http://www.jci.org Volume 119 Number 7 July 2009
be the first step, followed by pore-complex assembly and lamin
The nuclear lamina was initially thought to mainly provide
structural scaffolding for the nuclear envelope, but over the
years, numerous studies have implicated lamins in a wide range
of functions. In human cells, lamins exist in the nucleoplasm as
well as in association with the nuclear envelope (18) and they
have been implicated in regulating DNA replication and tran-
scription (19). The nuclear lamins, via interactions with SUNs,
inner nuclear–membrane proteins that bind to outer nuclear–
membrane proteins known as nesprins, also function as part of
a structural network connecting the nucleus to the cytoplasm
(20) (Figure 1). How these different functions of lamins relate
to disease pathophysiology is not clear.
Posttranslational processing of nuclear lamins. Except for lamin
C, mammalian lamins terminate with a CaaX motif (where C
is a cysteine, a is often an aliphatic amino acid, and X is one of
many different residues). The CaaX motif triggers three sequen-
tial enzymatic modifications (21, 22) (Figure 2). First, a 15-car-
bon farnesyl lipid is added to the cysteine residue by protein
The nuclear lamina. (A) The nuclear lamina is a meshwork of IFs localized primarily to the nucleoplasmic face of the inner nuclear membrane
(shown schematically in red). The lamins interact with several integral proteins of the inner nuclear membrane, including lamin B receptor (LBR),
MAN1 (encoded by the LEMD3 gene), emerin, lamina-associated polypeptide 1 (LAP), LAP2β, small nesprin 1 isoforms, and SUNs. SUNs
interact with large nesprin 2 isoforms, integral proteins of the outer nuclear membrane, which also interact with actin, linking the nuclear lamina
to the cytoskeleton. (B) In humans, 3 genes encode nuclear lamins. LMNA on chromosome 1q21.2 encodes the A-type lamins, with prelamin A
and lamin C generated by alternative RNA splicing being the major somatic cell isoforms. Prelamin A has 98 unique amino acids and lamin C
6 unique amino acids at their carboxyl terminus (gray striping). LMNB1 on chromosome 5q23.3–q31.1 encodes lamin B1, and LMNB2 on chro-
mosome 19p13.3 encodes lamin B2, the somatic cell B-type lamins. All the lamins have conserved α-helical rod domains and variable head and
tail domains preceding and following the central rod domain. The nuclear localization signals are located in the tail domain (indicated in red).
Prelamin A, lamin B1, and lamin B2 have carboxyl-terminal CaaX motifs, a signal for protein farnesylation.
?The?Journal?of?Clinical?Investigation http://www.jci.org Volume 119 Number 7 July 2009
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