?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
farnesyltransferase (FTase) (21, 22). After protein farnesylation,
which is one form of protein prenylation, the last three amino
acids (the –aaX) are clipped off by an endoprotease specific for
prenylated proteins. For lamin B1 and many other CaaX pro-
teins, this proteolytic processing step is carried out by RCE1
homolog, prenyl protein peptidase (RCE1) (23). For prelamin A,
this step is likely a redundant function of RCE1 and zinc metal-
lopeptidase, STE24 homolog (ZMPSTE24) (24–26). Next, the
newly exposed farnesylcysteine is methylated by a membrane
methyltransferase, isoprenylcysteine carboxyl methyltransferase
(ICMT) (27, 28). B-type lamins undergo no further modifica-
tions and retain a farnesylcysteine α-methyl ester at the carboxyl
terminus. In the case of prelamin A, the last 15 amino acids of
the protein, including the farnesylcysteine α-methyl ester, are
clipped off and degraded, leaving mature lamin A (25, 29, 30)
(Figure 2). This final endoproteolytic processing step does not
occur in the absence of ZMPSTE24 (24, 31), which very probably
carries out this reaction (26). Early studies suggested that the
final endoproteolytic processing step required methylation of
the farnesylcysteine (24, 32), but follow-up studies revealed that
lamin A biogenesis is only modestly affected by the absence of
methylation (33). Defining the biochemistry and enzymology of
CaaX-motif modifications involved contributions from diverse
disciplines, and the history of this topic has been covered else-
where (21, 22, 25, 34).
Why does nature go to the trouble of modifying the CaaX
motif of prelamin A, given that the carboxyl terminus of this
protein is clipped off and degraded? We believe that the most
likely explanation is that the CaaX-motif modifications ren-
der prelamin A more hydrophobic, facilitating its targeting to
the inner nuclear membrane, where ZMPSTE24 likely releases
mature lamin A (35). Farnesylation and methylation increase the
hydrophobicity of peptides (36), and Hennekes and Nigg (37)
showed that farnesylated prelamin A peptides bind to membrane
fractions. The idea that the final cleavage step in lamin A bio-
genesis occurs at the nuclear lamina was supported by Ottaviano
and Gerace (38), who found that a substantial fraction of newly
synthesized prelamin A is incorporated into a Triton X-100–
insoluble fraction, presumably the nuclear lamina, before its
conversion to mature lamin A. Further, a very recent study
showed that ZMPSTE24 is located both at the inner nuclear
membrane and the ER but suggested that the nucleus is the
major site of prelamin A processing (39). However, at this point,
no one can exclude the possibility that some prelamin A under-
goes processing in the ER.
While prelamin A processing could assist in the delivery of
lamin A to the nuclear rim, the processing steps may not be
absolutely essential for this process. Michael Sinensky’s group
found that a “mature lamin A” variant (where lamin A is syn-
thesized directly, bypassing all processing steps) reaches the
nuclear periphery normally (40). Hennekes and Nigg (37) also
found that mature lamin A reaches the nuclear periphery but
with delayed kinetics.
Diseases related to the nuclear lamina
Since 1999, at least 12 disorders have been linked to LMNA muta-
tions. Several of these are probably the same basic disease with vari-
ations in severity or extent of organ system involvement. Human
diseases also have been associated with mutations in ZMPSTE24,
LMNB1, and LMNB2 and mutations in genes encoding proteins
that interact with lamins (Table 1).
LMNA. There are two forms of Emery-Dreifuss muscular dys-
trophy (EDMD), inherited in either an X-linked or autosomal
manner. They are characterized by a triad of muscle weakness
and wasting in a scapulohumeral-peroneal distribution; early
contractures of the elbows, ankles, and posterior neck; and, most
significantly, cardiomyopathy. Symptoms generally appear in the
first decade of life, with contractures often the first manifesta-
tion. Slowly progressive muscle weakness and wasting usually
begin during the second decade of life. Cardiomyopathy occurs
in nearly all cases, with the initial presentation usually being a
block in atrioventricular conduction followed by left ventricular
dilation and congestive heart failure.
In 1994, Bione et al. (41) identified emerin (EMD) as the gene
on chromosome Xq28 that is mutated in X-linked EDMD. EMD
encodes emerin, an integral protein that was localized to the
inner nuclear membrane (42, 43). Later, it was shown that emer-
in binds directly to A-type lamins (44). In 1999, Bonne et al. (45)
Schematic diagram outlining the posttranslational processing of nucle-
ar lamins. Prelamin A and B-type lamins undergo 3 sequential post-
translational processing steps. First, the cysteine of the carboxyl-ter-
minal CaaX motif is farnesylated by protein FTase. Second, the –aaX
is clipped off. For prelamin A, this is likely a redundant activity of RCE1
and ZMPSTE24. Third, the newly exposed carboxyl-terminal farnesyl-
cysteine is methylated by isoprenylcysteine carboxyl methyltransferase
(ICMT). Prelamin A undergoes another step in which the carboxyl-ter-
minal 15 amino acids, including the farnesylcysteine methyl ester, are
clipped off by ZMPSTE24 and degraded, generating mature lamin A.
In the setting of ZMPSTE24 deficiency, the final endoproteolytic cleav-
age does not occur, leading to the accumulation of a farnesylated
and methylated prelamin A. ZMPSTE24 deficiency causes a severe
progeroid disorder, RD. In HGPS, an alternative splicing event results
in a 50–amino acid deletion in prelamin A, removing the site for the
final endoproteolytic cleavage step. Thus, mature lamin A cannot be
produced, and cells accumulate a mutant prelamin A that terminates
with a farnesylcysteine α-methyl ester.
1828? The?Journal?of?Clinical?Investigation http://www.jci.org Volume 119 Number 7 July 2009
Diseases caused by mutations in genes encoding lamins and associated proteins
Autosomal dominant EDMD
Autosomal recessive EDMD
Cardiomyopathy dilated 1A
Limb-girdle muscular dystrophy type 1B
Congenital-type muscular dystrophy
“Heart-hand” syndrome (with limb defects)
Lipoatrophy with diabetes, hepatic
steatosis, hypertrophic cardiomyopathy,
and leukomelanodermic papules
(also has features of progeria)
Acquired partial lipodystrophy
Atypical Werner syndrome
(also has partial lipodystrophy)
Charcot-Marie-Tooth disorder type 2B1
Pelger-Huet anomaly (heterozygous)/
syndrome, nonsporadic melorheostosis
Autosomal recessive cerebellar ataxia
Muscle weakness and wasting in scapulohumeral-peroneal distribution; early
joint contractures; dilated cardiomyopathy
Muscle weakness and wasting in scapulo-humeral peroneal distribution; early
joint contractures; dilated cardiomyopathy
Cardiomyopathy with minimal to no skeletal muscle involvement
Muscle weakness and wasting in limb-girdle distribution; dilated cardiomyopathy
Severe relatively diffuse myopathy presenting in first year of life; later cardiomyopathy
Brachydactyly with mild hand and more severe foot involvement; cardiomyopathy
Muscle weakness and wasting in scapulo-humeral peroneal distribution; early joint
contractures; and dilated cardiomyopathy
Loss of subcutaneous fat from the extremities at puberty, followed by increased fat
accumulation in the face and neck; insulin resistance; diabetes mellitus;
hyptertriglyceridemia; hepatic steatosis
Generalized fat loss; insulin-resistant diabetes, hypertriglyceridemia, hepatic steatosis,
hypertrophic cardiomyopathy; disseminated whitish papules
Hypoplastic mandible with dental crowding, acroosteolysis, stiff joints, atrophy of
the skin over hands and feet, hypoplastic clavicles; “Andy Gump” appearance;
persistently wide cranial sutures and multiple wormian bones; alopecia and short
stature; and partial lipodystrophy
Progressive, sporadic lipodystrophy with phenotype similar to FPLD2 (above)
Children appear aged; retarded growth; micrognathia; reduced subcutaneous fat;
alopecia; skin mottling; osteoporosis; and premature occlusive vascular disease
Various combinations of signs and symptoms including an aged appearance;
short stature; cataracts; sclerodermatous skin; osteoporosis; vascular disease
Partial lipodystrophy features along with osteolytic lesions in bone similar to
those found in HGPS
Perinatal lethal; tight skin; loss of fat; prominent superficial vasculature;
dysplastic clavicles; sparse hair; and multiple joint contractures
LMNA Wasting and weakness of the lower distal limbs; and lower limb areflexia
Symmetrical widespread myelin loss in the CNS; phenotype similar to that of
chronic progressive multiple sclerosis
Pelger-Huet anomaly: benign blood disorder of hyposegmented neutrophil nuclei;
HEM: generally prenatal/perinatal lethal with fetal hydrops; short limbs; and
abnormal chondroosseous calcification
Hyperostosis of cortical bone; dermatofibrosis in Buschke-Ollendorff syndrome
Dysarthria and ataxia; dysmetria; and brisk lower-extremity tendon reflexes
Early onset symptoms variably including twisted postures; turning in of the foot
or arm; muscle spasms; and jerking movements
HEM, hydrops-ectopic calcification motheaten; LBR, lamin B receptor; LEMD3, LEM domain–containing protein 3, also known as MAN1; SYNE1,
spectrin repeat containing nuclear envelope 1, also known as nesprin-1; TOR1A, torsin family 1, member A; TMPO, thymopoietin, also known as
lamina-associated polypeptide 2.
?The?Journal?of?Clinical?Investigation http://www.jci.org Volume 119 Number 7 July 2009
demonstrated that mutations in LMNA cause autosomal domi-
nant EDMD. LMNA mutations have also been identified in cases
of autosomal recessive EDMD (46). Soon thereafter, other stud-
ies showed that LMNA mutations cause dilated cardiomyopathy
with conduction defect type 1 (47) and limb-girdle muscular
dystrophy type 1B (48). Patients with these autosomal dominant
disorders have dilated cardiomyopathy but either little skeletal
muscle involvement or involvement in a limb-girdle distribu-
tion. These disorders, traditionally classified separately based
on clinical criteria, can be caused by the same LMNA mutation
and can even occur within the same family (49). Hence, auto-
somal EDMD, limb-girdle muscular dystrophy type 1B, and
dilated cardiomyopathy with conduction defect type 1 can be
considered variants of the same disease — with dilated cardiomy-
opathy and variable skeletal muscle involvement. More recently,
LMNA mutations have been shown to cause a congenital muscu-
lar dystrophy (50) and “heart-hand” syndrome (51), expanding
the range of muscle diseases linked to mutant A-type lamins.
Most LMNA mutations causing striated muscle diseases change
amino acid residues in lamins A and C, and these amino acid
changes can be located throughout the length of these proteins
(52). Short deletions, truncating mutations, splicing mutations,
and haploinsufficiency can also cause muscle disease (45, 52).
Dunnigan-type familial partial lipodystrophy (FPLD2), also
known as Dunnigan-Köbberling syndrome, is an autosomal domi-
nant disorder leading to peripheral loss of adipose tissue. Patients
are born with normal fat distribution, but at puberty they devel-
op loss of subcutaneous adipose tissue in the extremities, which
produces a muscular appearance, followed by increased adipose
tissue accumulation in the face and neck. Visceral fat depots are
unaffected or increased. Metabolic manifestations of FPLD2 are
insulin resistance, frequently leading to type II diabetes mellitus,
and hypertriglyceridemia. These metabolic abnormalities are
associated with premature atherosclerosis in some subjects (53).
Nearly all individuals with FPLD2 develop hepatic steatosis and
may be at increased risk for steatohepatitis (54). Although the dis-
ease is autosomal dominant and affects both sexes, the phenotype
is easier to discern and may be more severe in women, so there are
more female probands (55, 56).
Cao and Hegele (57) and Shackleton et al. (58) reported in 2000
that FPLD2 is caused by mutations in LMNA. Speckman et al. (59)
and Vigouroux et al. (55) soon reported additional FPLD2 patients
with LMNA mutations. Rare patients with LMNA mutations have
been reported that have lipodystrophy syndromes somewhat dif-
ferent than typical FPLD2 in combination with cardiac, skeletal
muscle, and other abnormalities (60–62).
While LMNA mutations causing muscle diseases are scattered
throughout LMNA, approximately 90% of mutations causing
FPLD2 are located in exon 8, most commonly within codons 482
and 486 (55, 57–59). Exon 8 encodes a globular domain common
to lamins A and C that forms an immunoglobulin-like fold (63,
64). Myopathy-causing missense mutations in this same domain
disrupt the three-dimensional structure of the fold. In contrast,
FPLD2 mutations do not disrupt the structure of the domain but
alter the charge of solvent-exposed surfaces (63, 64). Mutations
in exon 11 of LMNA (in particular codons 582 and 584), a region
unique to lamin A, also cause FPLD2, but less frequently (55, 59).
Hutchinson-Gilford progeria syndrome (HGPS) is a rare pedi-
atric progeroid syndrome that has captivated the news media,
clinicians, and basic scientists. Children with HGPS appear aged
and exhibit retarded growth, micrognathia, reduced subcutane-
ous fat, alopecia, skin mottling, osteogenic lesions in bone, and
osteoporosis. Patients have an increased susceptibility to arterial
occlusions, the pathogenesis of which is unclear. The generally
held assumption has been that the vascular occlusions are due
to atherosclerosis. However, plasma cholesterol levels are normal
in individuals with HGPS, and some characteristics of the vessel
wall biology in individuals with HGPS are different from those of
run-of-the-mill atherosclerosis (65, 66). Thus, it is possible, and
perhaps likely, that the vascular occlusions in HGPS are not due
to classical atherosclerosis.
HGPS is caused by de novo point mutations that interfere with
conversion of farnesyl–prelamin A to mature lamin A (67, 68).
The most common mutation is a point mutation in exon 11 (67,
68) that does not alter an amino acid (G608G) but optimizes an
alternative splice donor site, resulting in an in-frame deletion of
50 amino acids near the carboxyl terminus of prelamin A (67, 68).
Other LMNA point mutations associated with HGPS promote the
same aberrant splicing event (67, 69). The 50–amino acid deletion
leaves the CaaX motif intact; thus, the mutant prelamin A, gener-
ally called progerin, undergoes farnesylation and carboxyl meth-
ylation (70). However, the site for the final ZMPSTE24-mediated
endoproteolytic cleavage is eliminated (25), preventing further
processing to lamin A (71) (Figure 2). Most farnesylated progerin
is targeted to the nuclear envelope, although a portion seems to be
located in the nucleoplasm (72).
Although typical HGPS almost always involves the accumula-
tion of farnesylated progerin, very similar progeroid syndromes
can be caused by missense mutations in LMNA that are not
known to be associated with defective prelamin A processing.
For example, Verstraeten et al. (73) showed that compound het-
erozygosity for T28M and M540T mutations caused a progeroid
syndrome similar to HGPS. In addition, mandibuloacral dyspla-
sia, a progeroid disorder characterized by lipodystrophy and vari-
ous bony abnormalities, can be caused by a homozygous R527H
mutation (74). How these missense mutations lead to progeroid
syndromes requires more investigation.
LMNA mutations can also affect peripheral nerves. A homozy-
gous R298C substitution in lamin A and lamin C has been identi-
fied in Algerian families with Charcot-Marie-Tooth disease type
2B1 (75). Affected subjects have weakness and wasting of the dis-
tal lower limb muscles, and there is areflexia in the lower limbs.
Motor nerve conduction velocities are normal or only slightly
reduced in this axonal (nondemyelinating) neuropathy. Subjects
with LMNA haploinsufficiency sometimes have axonal neuropa-
thy along with muscular dystrophy/cardiomyopathy (76, 77). Vir-
tually nothing is known about how alterations in A-type lamins
cause this type of neuropathy.
The only reported human with complete deficiency of A-type
lamins (due to homozygous nonsense mutations in LMNA) exhib-
ited perinatal lethality (78). The preterm infant was smaller than
expected for gestational age, died of respiratory failure immedi-
ately after birth, and had a slightly dysmorphic face with retrog-
nathia, severe contractures of the limbs, contractures of the fingers
and the toes, fractures of the femur and arm, and generalized mus-
cular dystrophy. Hence, some A-type lamin function or functions
appear to be necessary for postnatal survival in humans.
ZMPSTE24. Restrictive dermopathy (RD), a perinatal-lethal
progeroid syndrome, is caused by loss of ZMPSTE24 and is associ-
ated with the accumulation of farnesylated prelamin A (Figure 2).
1830?The?Journal?of?Clinical?Investigation http://www.jci.org Volume 119 Number 7 July 2009
RD is characterized by tight skin, loss of fat, prominent super-
ficial vasculature, dysplastic clavicles, sparse hair, and multiple
joint contractures. Navarro et al. (79) initially proposed that RD
was caused by heterozygous mutation of ZMPSTE24 in associa-
tion with a mutation in another gene. Ultimately, Moulson et al.
(80) and Navarro et al. (81) showed that RD results from homo-
zygous loss of ZMPSTE24. Progeroid syndromes less severe than
RD, in some cases classified as mandibuloacral dysplasia, can be
caused by ZMPSTE24 missense mutations associated with resid-
ual enzymatic function (82, 83). Also, one patient with homozy-
gous loss of ZMPSTE24 exhibited phenotypes milder than those
in typical RD patients (84); that subject was heterozygous for a
truncating mutation in LMNA that eliminated the CaaX motif
of prelamin A. This genetic observation strongly suggests that
the farnesylated form of prelamin A is responsible for the dis-
ease phenotypes of RD.
LMNB1 and LMNB2. Only two disorders have thus far been
linked to modifications in the genes that encode the B-type
lamins. First, Padiath et al. (85) identified an LMNB1 duplica-
tion in four families with adult-onset autosomal dominant leu-
kodystrophy, a slowly progressive and fatal disorder character-
ized by pyramidal and cerebellar dysfunction and symmetrical
demyelination of the CNS. Overexpression of lamin B1 in the
eye of Drosophila causes a degenerative phenotype (85). Sec-
ond, Hegele’s group (86) identified three heterozygous LMNB2
point mutations, two causing amino acid substitutions, in nine
patients with acquired partial lipodystrophy (also known as Bar-
raquer-Simons syndrome). Because these mutations were rare in
a control population, the authors suggested that they might be
etiologically important in the pathogenesis of acquired partial
lipodystrophy. However, no functional studies were performed.
Thus far, there have been no associations between human diseas-
es and loss-of-function mutations in either LMNB1 or LMNB2,
suggesting either that these proteins serve redundant functions
or that loss of these genes causes embryonic lethality. The latter
explanation seems more likely, given that Lmnb1 deficiency in
mice is perinatal lethal (87).
Abnormal nuclear morphology in laminopathies
To gain insights into the pathogenesis of laminopathies, many
investigators began by looking at the most obvious cellular
abnormality — misshapen cell nuclei. Indeed, during the past
few years, alterations in nuclear morphology induced by lamin
abnormalities have received considerable attention. Most studies
on how mutant lamins affect nuclear morphology have involved
dermal fibroblasts from human patients, fibroblasts from mice
with targeted Lmna mutations, or cultured cells that overexpress
a mutant lamin protein. Since the initial reports (using fibro-
blasts from Lmna–/– mice, transfected cells expressing A-type
lamin variants detected in individuals with EDMD/cardiomy-
opathy and FPLD2, and fibroblasts from human subjects with
FPLD2; refs. 88–91), there have been many others that have cov-
ered virtually all the laminopathies and been reviewed elsewhere
(25, 52, 92). The consensus from such studies is that when A-type
lamins are absent from cells that normally express them, nuclei
are irregular in shape with herniations of the nuclear envelope,
nuclear pore complexes cluster slightly, B-type lamins are lost
from one nuclear pole, and emerin mislocalizes from the inner
nuclear membrane to the bulk ER. Numerous studies (reviewed
in refs. 25 and 52) have reported morphological alterations in
cells expressing A-type lamin variants, which, depending on the
cell type or mutation, have been described as lobulation (also
known as blebbing) of the nuclear envelope, honeycombing of the
lamina, increased nuclear surface area, thickening of the nuclear
lamina, aberrant intranuclear foci of lamins with a decrease at
the nuclear periphery, loss of peripheral heterochromatin, and
aberrant clustering of nuclear pore complexes. Partial mislo-
calization of emerin is also observed in cells expressing some
A-type lamin variants. Some variants with amino acid substi-
tutions have altered dynamics in the nucleus compared with
wild-type lamin A. Cells lacking A-type lamins also exhibit defec-
tive nuclear mechanics, and some A-type lamin variants cause
increased susceptibility to heat shock. Nuclei of Zmpste24-defi-
cient mouse fibroblasts are misshapen, with blebs and hernia-
tions of heterochromatin. Fibroblasts from lamin B1–deficient
mice have severely abnormal nuclear morphology with multiple
nuclear blebs. Overexpression of B-type lamins induces nuclear
membrane growth and the formation of abnormal intranuclear
membrane structures, which appear to depend on the presence
of a CaaX motif.
Despite numerous reports of abnormal nuclear structure caused
by defects in A-type lamins, the significance of these morphologi-
cal abnormalities to the pathogenesis of disease is unclear. Nucle-
ar abnormalities are generally present only in a subset of fibro-
blasts, and the percentage of misshapen nuclei depends upon
culture conditions, cell density, and passage number. There is no
clear association of any specific morphological abnormality with
any particular disease. Also, structural alterations in the lamins
could lead to abnormalities in other nuclear structures, perturb-
ing nuclear functions not directly linked to structural abnormali-
ties in the nuclear envelope. In any case, the presence of morpho-
logical alterations suggests that the mechanical properties of the
nuclear lamina are altered, and indeed this has been demonstrated
clearly in cells lacking A-type lamins (93, 94). Nuclear morphol-
ogy in cells expressing either farnesylated prelamin A or progerin
can be improved by drugs that block protein farnesylation, and
those same drugs improve the whole-animal phenotypes in mice
lacking ZMPSTE24 and in mice with HGPS (95–99) (see below).
However, in these cases, a cause and effect relationship between
improved nuclear shape and improved disease phenotypes has
never been established.
Pathogenic mechanisms of laminopathies and potential
How mutations in LMNA cause diverse diseases is poorly under-
stood and is one of the most intriguing riddles in medical genetics.
However, recent studies have suggested some insights into the cel-
lular pathogenesis of two LMNA-related disorders, cardiomyopa-
thy and progeria, and those insights have led to studies on poten-
tial therapies for these diseases. These studies have relied heavily
on the use of genetically modified mouse models (see Sidebar 1 for
descriptions of several mouse models relevant to this Review).
Cardiomyopathy. Although cardiomyopathy and muscular dys-
trophy were the first phenotypes found in human subjects with
LMNA mutations, the pathogenic mechanisms underlying these
phenotypes have been obscure. To approach this issue, Muchir
et al. (100) used microarrays to identify genes and pathways that
were perturbed in hearts of LmnaH222P/H222P mice (a mouse model
of autosomal EDMD in which a single missense LMNA muta-
tion [H222P] known to cause autosomal EDMD in humans is
? The?Journal?of?Clinical?Investigation http://www.jci.org Volume 119 Number 7 July 2009
introduced into Lmna). They detected activation of the ERK and
JNK branches of the MAPK signaling cascade, and these changes
occurred prior to the onset of histopathologic abnormalities in
the heart. Furthermore, expression of mutant forms of lamin A in
cultured cells led to activation of ERK and JNK signaling. These
findings were consistent with the known alterations in MAPK
signaling in cardiomyopathy (101). Muchir et al. (102) further
analyzed gene-expression profiles in hearts of Emd-knockout
mice, a model of X-linked EDMD, and found a similar molecular
signature — activation of ERK and its downstream targets. Thus,
MAPK signaling seems relevant to the pathogenesis of heart dis-
ease in both X-linked and autosomal dominant EDMD. However,
it remains unclear how abnormalities in the nuclear envelope lead
to activation of ERK and/or JNK.
Pharmacological inhibitors of MEK (the MAPK kinase that
activates ERK) can be administered systemically, and some have
been tested as anticancer agents in early-stage human clinical
trials. The availability of these agents led Muchir et al. (103) to
hypothesize that systemic administration of a MEK inhibitor
would prevent dilated cardiomyopathy in LmnaH222P/H222P mice.
Beginning at 8 weeks of age, prior to the onset of detectable
cardiomyopathy, LmnaH222P/H222P mice were treated with a MEK
inhibitor. At 16 weeks of age, nontreated and placebo-treated
LmnaH222P/H222P mice manifested increased left ventricular end-
systolic and end-diastolic diameters as well as a 30% reduction in
ejection fraction. In contrast, hearts of LmnaH222P/H222P mice treat-
ed with the MEK inhibitor were indistinguishable from those of
wild-type mice. Treatment with a MEK inhibitor also prevented
upregulation of genes encoding atrial natriuretic peptides. These
mouse studies suggest that ERK inhibition might hold promise
for treating cardiomyopathy in human subjects with LMNA and
EDM mutations (Figure 3).
Progeria. Although no single mechanism has emerged, several
studies point to defects in genome maintenance (e.g., defective
DNA repair, accumulation of DNA damage, and altered gene
expression) as underlying causes of the progeroid syndromes
(104). This also seems to be important in progerias associated
with ZMPSTE24 deficiency and specific LMNA mutations. Liu et
al. (105) reported that ZMPSTE24-deficient mouse fibroblasts
were more sensitive to DNA-damaging agents and were slow to
repair DNA and proposed that defective DNA repair was linked
to genome instability and cell senescence. DNA damage respons-
es are also abnormal in cells from subjects with HGPS, but treat-
ment with a protein FTase inhibitor (FTI), which blocks prenyl-
ation of progerin, did not reduce markers of DNA damage (106).
Varela et al. (107) used microarray analysis to identify a possible
link between ZMPSTE24 deficiency in mice and p53 activation.
Also, there was a suggestion that disease phenotypes were less
severe in Zmpste24–/–p53–/– mice (107), which would be consistent
with the notion that p53 overexpression promotes aging (108).
Shumaker et al. (109) showed that histone methylation patterns
are altered in HGPS, providing evidence that the lamina interacts
with chromatin to modulate heterochromatin and presumably
gene transcription. These changes preceded the appearance of
abnormally shaped nuclei.
Others have proposed that abnormal nuclear mechanics are
an important cellular defect in HGPS. Dahl et al. (110) investi-
gated the mechanical properties of the lamina in HGPS cells and
found that the nuclei of HGPS cells exhibited reduced deform-
ability when aspirated with a micropipette. They also found that
HGPS nuclei were more resistant to disruption by mechanical
pressure than the nuclei from wild-type cells. Verstraeten et al.
(111) showed that cultured dermal fibroblasts from patients
with HGPS developed progressively stiffer nuclei with increasing
passage number and exhibited decreased viability under repeti-
tive mechanical strain as well as attenuated wound healing. FTIs
reversed the nuclear stiffness phenotype and accelerated the
wound-healing response in fibroblasts from subjects with HGPS
and healthy controls but did not restore sensitivity to mechanical
strain. While these findings are clearly intriguing, there were no
Mouse models of laminopathies
Many mouse models have been extremely helpful in elucidating pathophysiology of laminopathies as well as for examining poten-
tial therapies. This topic has been reviewed elsewhere (92). The mouse models discussed in this review include:
Lmna-knockout mice (88). Lmna–/– mice develop regional muscular dystrophy and dilated cardiomyopathy mimicking
human EDMD early in life. Lmna+/– mice are normal at early ages but develop cardiomyopathy late in life (126).
Knockin mice with a H222P mutation in Lmna (127). LmnaH222P/H222P mice carry a single missense mutation known
to cause EDMD in humans. These mice develop muscular dystrophy and dilated cardiomyopathy.
Zmpste24-knockout mice (24, 31). Zmpste24–/– mice lack the prelamin A endoprotease that converts farnesyl-
prelamin A to mature lamin A. They accumulate farnesyl–prelamin A and develop many disease
phenotypes reminiscent of progeria.
HGPS-knockin mice (97). These mice carry a Lmna-knockin allele (LmnaHG) that yields progerin exclusively.
Heterozygous mice (LmnaHG/+) express large amounts of progerin and develop many disease phenotypes of progeria.
HGPS-knockin mice expressing a nonfarnesylated version of progerin (121). These mice carry a mutant Lmna allele
(LmnanHG) identical to the LmnaHG allele except that the cysteine of the CaaX motif was changed to a serine (this
mutation prevents protein prenylation). Heterozygous mice (LmnanHG/+) develop all of the disease phenotypes
observed in LmnaHG/+ mice, but the phenotypes are somewhat milder.
Lamin C–only mice (125). These mice carry a mutant Lmna allele that yields lamin C exclusively. Homozygous mice
(LmnaLCO/LCO) have no disease phenotypes.
1832? The?Journal?of?Clinical?Investigation http://www.jci.org Volume 119 Number 7 July 2009
obvious mechanisms connecting the defects in nuclear mechan-
ics to other cellular phenotypes or disease phenotypes.
Signaling pathways required for maintaining normal stem
cell function appear to be perturbed in cells expressing progerin
or high levels of unprocessed prelamin A. Scaffidi and Misteli
(112) showed that the expression of progerin activates down-
stream effectors of the Notch signaling pathway and alters the
differentiation potential of mesenchymal stem cells. Espada et
al. (113) showed that ZMPSTE24 deficiency caused an alteration
in the number and proliferative capacity of epidermal stem cells,
with alterations in molecular signaling pathways implicated in
the regulation of stem cells, such as Wnt and microphthalmia
transcription factor. These studies demonstrate a potential link
between stem cell dysfunction and progeria, but the precise
contribution of stem cells to the pathophysiology of progeria
remains to be established.
In considering the absence of disease phenotypes in Zmpste24–/–
Lmna+/– mice, Fong et al. (95) hypothesized that the farnesylated
form of prelamin A might be the molecular culprit in progeria.
They further reasoned that blocking protein farnesylation might
interfere with progerin targeting to the nuclear periphery, poten-
tially reducing its toxic effects. In support of this hypothesis,
Yang et al. (72) showed that FTI treatment mislocalized progerin
away from the nuclear periphery and reduced the frequency of
misshapen nuclei in LmnaHG/+ fibroblasts (i.e., fibroblasts from
mice in which a mutant Lmna allele, LmnaHG, encodes progerin
exclusively). Shortly thereafter, Toth et al. (114) showed that
an FTI reduced the frequency of misshapen nuclei in cultured
fibroblasts from humans with HGPS and ZMPSTE24 deficien-
cy as well as in fibroblasts from Zmpste24–/– mice (114). Several
other laboratories reported the same basic findings, some using
complementary approaches and different systems (115–118). In
the studies by Yang et al. (72) and Toth et al. (114), blockade of
protein farnesylation was substantial, as farnesylation of human
DnaJ homolog-2 (HDJ-2) (an unrelated CaaX protein) was largely
blocked and nonfarnesylated prelamin A accumulated in cells.
FTI treatment also reduced levels of lamin A and prelamin A
(114), suggesting that the blockade of protein farnesylation
might reduce the stability of prelamin A.
The next step was to examine whether an FTI might ameliorate
disease in mouse models of progeria. Fong and coworkers (96)
found that systemic administration of an FTI improved body
weight curves in both male and female Zmpste24–/– mice, although
the drug also led to weight loss in wild-type mice. FTI administra-
tion also improved survival, improved grip strength performance,
and reduced the number of rib fractures. However, FTI-treated
Studies from LmnaH222P/H222P knockin mice and Emd-knockout mice suggest that activation of ERK and/or JNK underlies the development of
cardiomyopathy. Cardiomyocytes in normal hearts of wild-type mice exhibit detectable ERK and JNK activation, as judged by low levels of
expression of downstream transcription factors such as Elk1, Elk4, Aft2, and Aft4 (left panel). Both ERK and JNK signaling are increased in
hearts from mice harboring the H222P point mutation in Lmna, whereas ERK is activated in hearts of Emd-knockout mice (red arrows; middle
panel). Phosphorylation and nuclear translocation of ERK and JNK modulate gene expression, leading to dilated cardiomyopathy (middle panel).
Currently, it is unclear how alterations in A-type lamins or the loss of emerin lead to the activation of ERK and/or JNK. Studies in LmnaH222P/H222P
mice have shown that pharmacological inhibition of MEK, the kinase that phosphorylates ERK, can prevent the development of cardiomyopathy
at 16 weeks of age (right panel).
?The?Journal?of?Clinical?Investigation http://www.jci.org Volume 119 Number 7 July 2009
Zmpste24–/– mice still had profound disease phenotypes and suc-
cumbed to the progeroid disease. In these studies, only 10%–50%
of the HDJ-2 in tail extracts was nonfarnesylated (similar to lev-
els observed in the testing of FTIs as anticancer agents). The FTI
also led to the appearance of nonfarnesylated prelamin A in tissue
extracts but to a lower extent than in cell culture experiments (96).
LmnaHG/+ mice treated with an FTI also exhibited improvements in
body weight curves, weights of fat depots, bone fractures, and bone
mineralization (97, 99). However, as in Zmpste24–/– mice, improve-
ments in disease phenotypes fell far short of a cure. In these stud-
ies, more than 50% of HDJ-2 in livers of FTI-treated mice was non-
farnesylated, and small amounts of nonfarnesylated prelamin A
accumulated in tissues (97, 99). Increasing FTI doses led to greater
effects on farnesylation, but survival was adversely affected, pre-
sumably because of drug toxicity (99).
The efficacy of FTIs in reducing the number of cells with mis-
shapen nuclei (72, 114) and in ameliorating disease phenotypes in
mouse models of progeria (96, 97, 99) prompted an open-label trial
of an FTI (lonafarnib) in children with HGPS (119). The trial has
been ongoing for more than a year, but neither clinical outcomes
nor evidence regarding the in vivo blockade of protein farnesyl-
ation are available. In the human trial, lonafarnib is being adminis-
tered to children with advanced disease phenotypes, a substantial
difference from the mouse experiments, where the drug therapy
was initiated prior to development of significant disease.
The improvements in nuclear shape in FTI-treated HGPS fibro-
blasts have in some cases been quite striking (72, 116). However,
the benefits of FTIs in LmnaHG/+ mice, although highly statistically
significant, have been less dramatic. One possible explanation is
that the degree of inhibition of protein FTase was less than com-
plete in the mice. Another possibility is that prelamin A can be
alternately prenylated by geranylgeranyltransferase-I (GGTase-I)
when FTase is blocked. The latter possibility is very plausible, as
lamins terminate with methionine and other CaaX proteins termi-
nating with methionine can be geranylgeranylated when FTase is
blocked (120). Varela et al. (98) used mass spectrometry (MALDI-
TOF) to examine prelamin A and progerin structure in FTI-treat-
ed cells and uncovered strong evidence that these proteins are
geranylgeranylated in FTI-treated fibroblasts. Whether alternate
geranylgeranylation of prelamin A also occurred in FTI-treated
mice was never investigated. Varela et al. (98) also reported that a
combination of a GGTase-I inhibitor and an FTI increased prela-
min A accumulation in cultured fibroblasts, again consistent with
alternate prenylation. On the other hand, another group found
that an FTI retards the electrophoretic migration of prelamin A,
raising the possibility that the extent of alternate prenylation may
be limited (or that the FTIs that were used are effective in block-
ing protein geranylgeranylation) (114). More studies are clearly
required to define the extent of alternate prenylation in vivo in the
setting of FTI therapy and to explore its potential relevance to the
pathogenesis of progeria.
Another possible explanation for the incomplete therapeutic
response with an FTI in LmnaHG/+ mice is that it leads to accumu-
lation of another abnormal lamin—nonfarnesylated progerin. If
the nonfarnesylated progerin were itself toxic to cells, the ben-
efits of FTI therapy would obviously be limited. To explore the
possibility that nonfarnesylated progerin is toxic and capable of
eliciting disease, Yang et al. (121) created knockin mice express-
ing nonfarnesylated progerin (LmnanHG/+). LmnanHG/+ mice are
genetically identical to LmnaHG/+ mice, except that the cysteine
in the CaaX motif of progerin was changed to serine, eliminat-
ing all protein prenylation. LmnanHG/+ mice exhibited the same
phenotypes as LmnaHG/+ mice, but they were slightly milder. In
addition, fewer LmnanHG/+ fibroblasts contained misshapen nuclei
(121). A likely explanation for the milder phenotypes in LmnanHG/+
mice was that steady-state cellular levels of progerin were lower
in LmnanHG/+ than LmnaHG/+ mice (121). The milder phenotypes
in LmnanHG/+ mice (compared with LmnaHG/+ mice) are consistent
with the results of FTI treatment studies (97, 99) and support
the idea that inhibiting protein farnesylation could be beneficial.
On the other hand, finding that nonfarnesylated progerin caused
substantial disease suggested that there could be significant limi-
tations in the FTI treatment strategy for HGPS.
Toth et al. (114) suggested that bisphosphonates, frequently pre-
scribed for osteoporosis, might be useful for treating bone disease
in progeria. Nitrogen-containing bisphosphonates bind avidly to
bone and block farnesyl diphosphate synthase, an enzyme that
produces farnesyl diphosphate (122). Inhibiting synthesis of
farnesyl diphosphate blocks protein farnesylation, protein gera-
nylgeranylation, and cholesterol synthesis, and these effects are
thought to promote apoptosis in osteoclasts, leading to improved
bone density. It is not clear that increased activity of osteoclasts
underlies bone disease of progeria (25), and it seems somewhat
more probable that dysfunctional osteoblasts are more important
for the pathogenesis of disease (24, 25). In any case, Toth et al.
(114) showed that one of the nitrogen-containing bisphospho-
nates, alendronate, inhibited prelamin A processing in wild-type
and HGPS fibroblasts, although the blockade of lamin A biogen-
esis was less than with an FTI. The impact of these drugs on prela-
min A processing in vivo (in mouse or humans) is not yet clear. A
potential advantage of bisphosphonates is that they would inter-
fere with geranylgeranylation by GGTase-I, if indeed this enzyme
were active in the posttranslational modification of prelamin A in
vivo. Another advantage of bisphosphonates is that these drugs are
concentrated in bone, a tissue that is severely affected in progeria.
On the other hand, it seems unlikely that these drugs would be
helpful for treating disease phenotypes unrelated to bone, such as
lipodystrophy and vascular disease.
Varela et al. (98) tested a combination of a potent nitrogen-
containing bisphosphonate and a statin in Zmpste24–/– mice and
documented improved survival and improvements in bone abnor-
malities. The rationale for this drug combination was to inhibit
prelamin A farnesylation in a synergistic manner and also to block
any alternate geranylgeranylation that might occur in the tissues
of mice. Although it is clear that the mice treated with the drug
combination exhibited an improvement in disease phenotypes,
they did not report whether the drug combination actually affect-
ed the prenylation of prelamin A (or any other protein) in the tis-
sues of mice; thus, the mechanism for the observed improvements
in disease phenotypes is not yet entirely clear. Varela et al. (98) did
not find a beneficial effect of a statin alone or a bisphosphonate
alone on the survival of Zmpste24–/– mice, although the number of
mice in the latter experiments was small.
Blocking protein prenylation with an FTI represents a “blunt
instrument” for the treatment of HGPS, in that FTIs block the
posttranslational processing of many CaaX proteins, includ-
ing the B-type lamins. Similarly, the bisphosphonate/statin
combination would inhibit the processing of both farnesyl-
ated and geranylgeranylated proteins, at least in bone. A more
specific approach would be to identify therapies that interfere
1834? The?Journal?of?Clinical?Investigation http://www.jci.org Volume 119 Number 7 July 2009
with the proximal cause of HGPS — the utilization of the alter-
nate splice donor site in exon 11 of LMNA. Scaffidi and Misteli
(123) transfected HGPS fibroblasts with a morpholino oligo-
nucleotide directed against the abnormal splice donor site and
found reduced levels of progerin in cells, reduced frequency of
misshapen nuclei in fibroblasts, and normalized expression of
aberrantly expressed genes. Huang et al. (124) tested an RNA
interference approach to reduce levels of progerin in HGPS cells.
They identified a short hairpin RNA directed against sequences
unique to progerin that reduced progerin transcripts and pro-
tein levels by approximately 25%. Despite this modest effect,
the frequency of misshapen nuclei was reduced and cell prolif-
eration rates increased. Another strategy was suggested by the
absence of disease in mice carrying two Lmna alleles that exclu-
sively produce lamin C (LmnaLCO/LCO mice, so called lamin C–only
mice) (125). If lamin A and prelamin A are dispensable, it might
make sense to treat HGPS by eliminating all prelamin A tran-
scripts (both for progerin and wild-type prelamin A) with anti-
sense oligonucleotides. Fong et al. (125) identified an antisense
oligonucleotide that potently reduced prelamin A transcripts
and, when tested in fibroblasts from mice lacking ZMPSTE24,
reduced both prelamin A levels and the frequency of misshapen
nuclei. Thus far, no laboratory has tested oligonucleotide thera-
peutics in animal models.
Conclusion: laminopathies as rare disease models
of common conditions
Research on nuclear lamins and laminopathies provides a fasci-
nating example of an unexpected intersection between basic cell
biology and clinical medicine. During the next few years, we antici-
pate many more studies on disease pathogenesis and treatment
approaches. These studies are important because, although mono-
genic laminopathies are relatively rare, investigation of these dis-
orders is likely to yield important insights into cellular processes
involved in more common forms of cardiomyopathy, metabolic
disorders, and physiological aging.
We apologize to colleagues in this field that we could not cite
all of the important papers due to strict limitations on space
and numbers of references. The authors were supported by NIH
grants HL76839, CA099506, and AR050200 (to S.G. Young);
HL086683 (to L.G. Fong); AR048997, NS059352, and AG025240
(to H.J. Worman); Muscular Dystrophy Association grant
MDA4287 (to H.J. Worman); Ellison Medical Research Founda-
tion grant AGSS1678 (to S.G. Young); and March of Dimes grant
FY20071012 (to L.G. Fong).
Address correspondence to: Stephen G. Young, 650 Charles E.
Young Dr. South, Los Angeles, California 90095, USA. Phone: (310)
825-4934; Fax: (310) 206-0865; E-mail: email@example.com.
Or to: Howard J. Worman, College of Physicians and Surgeons,
Columbia University, 630 West 168th Street, 10th Floor, Room
508, New York, New York 10032, USA. Phone: (212) 305-8156;
Fax: (212) 305-6443; E-mail: firstname.lastname@example.org.
Antoine Muchir’s present address is: Santhera Pharmaceuticals
Ltd., Liestal, Switzerland.
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