Progeroid syndromes are heritable human disorders with
features that suggest premature ageing1. These syndromes
have been well characterized as clinical disease entities,
and in many instances the associated genes and causative
mutations have been identified. The identification of
genes that are associated with premature-ageing-like
syndromes has increased our understanding of molecu-
lar pathways that protect cell viability and function, and
has provided clues to the molecular mechanisms that
underlie normal human ageing. However, despite these
advances, little is understood about how the molecular
and cellular defects that result from mutations of progeria-
associated genes lead to organismal phenotypes that
resemble ageing. This lack of mechanistic understanding
has also hampered efforts to determine the relationship
between progeroid syndromes and normal ageing.
Many heritable human diseases are characterized
by progeroid features that recapitulate some features of
normal human ageing. One of the earliest compilations
of genetic syndromes with potential to reveal the patho-
biology of ageing was published in 1978 by Martin1.
Martin identified 162 syndromes, in a catalogue of
human genes and genetic diseases entitled Mendelian
Inheritance in Man (see Online Mendelian Inheritance
in Man in Further information), that showed different
degrees of phenotypic overlap with normal ageing.
These syndromes were further evaluated for the pres-
ence of 21 criteria such as chromosomal aberrations,
premature greying and loss of hair, an elevated risk of
cancer, diabetes mellitus or vascular disease. Notably,
none of the syndromes recapitulated all of the features
that are observed in normal ageing, and they were
therefore termed segmental, as opposed to global,
progeroid syndromes. Among the segmental progeroid
syndromes, the syndromes that most closely recapitu-
late the features of human ageing are Werner syndrome
(WS), Hutchinson–Gilford progeria syndrome (HGPS),
Cockayne syndrome, ataxia-telangiectasia, and the con-
stitutional chromosomal disorders of Down, Klinefelter
and Turner syndromes.
In this review we focus on two of the best character-
ized of these disorders, WS and HGPS . Both syndromes
show substantial phenotypic overlap with normal ageing,
and for each there has been recent progress in under-
standing the genetic, biochemical and cellular basis of the
disease. Mutations in WRN and LMNA genes give rise
to WS and HGPS, respectively. Functional roles of their
encoded gene products, WRN and A-type lamins, have
recently begun to emerge. We summarize new inform-
ation on functional roles of these proteins, and how
altered function may result in the cellular and organismal
phenotypes of WS and HGPS. Important unanswered
questions about the molecular pathogenesis of WS and
HGPS are outlined, and we discuss whether WRN and the
A-type lamins have a role in the biology of normal ageing
and age-associated disease.
A better understanding of the pathogenesis of these
two human progeroid syndromes is likely to improve
our picture of several areas of cell biology, most notably
in the areas of nuclear structure, dynamics and DNA
repair, as well as how defects in these fundamental bio-
logical processes lead to cellular and organismal disease
phenotypes. Other DNA-repair-deficiency syndromes
that have progeroid features — such as xeroderma
§Genome Sciences and the
¶Molecular and Cellular
Biology Program, University
of Washington, Seattle,
Washington 98195, USA.
Correspondence to B.K.K.
Werner and Hutchinson–Gilford
progeria syndromes: mechanistic
basis of human progeroid diseases
Brian A. Kudlow*¶, Brian K. Kennedy* and Raymond J. Monnat Jr‡§
Abstract | Progeroid syndromes have been the focus of intense research in part because
they might provide a window into the pathology of normal ageing. Werner syndrome and
Hutchinson–Gilford progeria syndrome are two of the best characterized human progeroid
diseases. Mutated genes that are associated with these syndromes have been identified,
mouse models of disease have been developed, and molecular studies have implicated
decreased cell proliferation and altered DNA-damage responses as common causal
mechanisms in the pathogenesis of both diseases.
MECHANISMS OF DISEASE
394 | MAY 2007 | VOLUME 8
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**** ******** * **
3′→5′ exonucleaseRecQ helicaseRQCHRDCNLS
* Non-synonymous SNP
pigmentosum and Cockayne syndrome — and defects in
the response to DNA-strand breaks have been recently
WS as a progeroid syndrome
WS is an autosomal recessive disease with features that are
reminiscent of premature ageing. The initial description of
WS by Werner in 1904 (REF. 3) emphasized four features:
short stature, bilateral cataracts, early greying and loss of
hair, and scleroderma-like skin changes. These pheno-
types have been observed in nearly all patients, including
those in a patient cohort that was recently studied by the
Werner Syndrome International Registry 4–7 (see Further
information). Clinical features of the syndrome appear
de novo (often beginning during the second decade
of life), are progressive and are not the consequence of
another systemic disease process or the result of a primary
endocrine deficiency or dysfunction4,8.
The clinical diagnosis of WS can be challenging in
light of the complex, progressive and variable nature of
the WS phenotype. This is particularly true in young
adults, in whom there might be few convincing signs or
no family history to raise suspicion. To aid the clinical
diagnosis of WS, a useful set of diagnostic criteria and
a scoring system have been developed by the Werner
Syndrome International Registry. These clinical criteria,
together with molecular approaches to identify common
WRN mutations or to document the loss of WRN protein,
can usually confirm or exclude a diagnosis of WS7,9.
The WRN gene: mutations and epigenetic silencing. The
chromosome 8p12 WRN gene was identified in 1996 by
positional cloning and encodes a 162-kDa RecQ helicase
protein10. The human RecQ helicase family consists
of 5 proteins, of which only WRN possesses 3′→5′
exo nuclease activity and 3′→5′ helicase activity
(reviewed in REFS 11,12). The WRN protein seems to
be ubiquitously expressed, and it can be detected by
western blot in cell lines and tissue samples from normal
individuals and, in reduced amounts, from heterozygous
carriers of single mutant copies of the WRN gene13–15.
However, there has been no systematic study of WRN
localization in different cell types or tissues during
embryonic development or in the adult.
All of the disease-associated WRN mutations7,9 (BOX 1)
confer a common biochemical phenotype: they lead to
truncation or, in one instance, apparent destabilization
and loss of WRN protein from patient cells13,14. These
biochemical data are consistent with the autosomal-
recessive inheritance of WS. The absence of patient-
derived missense mutations that selectively inactivate
the WRN helicase or exonuclease activity is notable.
These findings indicate that both biochemical activities
of WRN must be lost to promote WS pathogenesis16.
Individuals who carry single mutant-WRN alleles have
elevated genetic instability in vivo17, and cell lines from
heterozygous individuals have intermediate sensitivity
to DNA-damaging agents such as DNA-crosslinking
drugs and topoisomerase I inhibitors that selectively
kill WRN-deficient cells18,19. As WRN heterozygotes are
common worldwide20, it will be important to determine
whether heterozygous carriers are at increased risk of
disease or treatment-related toxicity after receiving
drugs such as cis-Pt or the topoisomerase I inhibitors
camptothecin or irinotecan.
The recent report of epigenetic silencing of the WRN
locus in human tumour-cell lines and tissue samples21
identifies another mechanism by which WRN expres-
sion might be regulated. This study clearly documented
the association between hypermethylation of the
WRN gene and loss of the WRN protein. Moreover, it
showed that WRN silencing led to increased sensitivity
Box 1 | Mutations and polymorphisms of WRN
The WRN protein has 1,432 amino-acid (aa) residues and contains four domains:
catalytically active 3′→5′ exonuclease and ATPase-helicase domains (exonuclease and
RecQ helicase segments) and two domains that are involved in DNA-substrate and protein
interactions (RQC and HRDC domains). A nuclear-localization signal (NLS) is located near
the C terminus of the protein.
The locations and molecular types of 58 mutations in the WRN gene that have been
reported in patients with Werner syndrome (WS) are also shown7,9. These published
examples have been assembled in the form of a web-accessible Locus-Specific Mutational Database (see Further
information). All of these mutations have a common biochemical consequence: they truncate WRN and lead to loss of the
WRN helicase and exonuclease activities. Patients with WS who fulfil the clinical diagnostic criteria for WS but lack WRN
mutations have also been identified. These rare WS ‘phenocopies’ might reflect persistent silencing of WRN expression
(see text) or help us to identify other genes that function with or regulate WRN. A large number of WRN single-nucleotide
polymorphisms (SNPs) have also been identified (see SNP linked to WRN in Further information). The functional
importance of almost all of these variants is unknown, although one coding-region non-synonymous variant (circled
asterisk) has been shown to markedly reduce the catalytic activity of WRN96. bp, base pair.
A protein with a domain that
contains sequence and
structural homology to the
Escherichia coli RecQ helicase.
Human RecQ helicase proteins
include WRN, BLM and REQ4.
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A potentially error-free DNA-
repair pathway in which DNA
double-strand breaks are
repaired by limited DNA
synthesis off a second,
undamaged DNA molecule (for
example, a sister chromatid)
followed by resolution and
religation of strand breaks.
A state of permanent cell-cycle
exit that often occurs as a
result of a cell exhausting its
replicative potential. It can also
result from cellular stresses or
activation of oncogenes.
A DNA-repair pathway that can
operate in all phases of the cell
cycle and that does not require
the presence of a homologous
DNA-repair template to repair
DNA double-strand breaks.
to topoisomerase I inhibitors and the DNA-crosslinking
drug mitomycin-C. Therefore, cells that lack WRN pro-
tein owing to epigenetic silencing of the WRN gene have
cellular phenotypes that resemble cells in which WRN
is absent owing to germline mutation. The study is also
consistent with increased cancer incidence in individuals
In vivo functions of WRN
The WRN helicase and exonuclease activities, first
predicted on the basis of protein homologies10,23,24, were
subsequently confirmed by several groups, and these
groups also defined in vitro substrate preferences. These
preferred WRN substrates include several types of 3- and
4-way DNA junctions as well as gapped, branched or
unpaired DNA and DNA overhangs. Protein-interaction
studies have also identified WRN-interacting proteins,
such as replication protein A (RPA), that have roles in
many aspects of DNA metabolism together with proteins
that are involved in specific DNA metabolic pathways
such as DNA replication, recombination or repair
(reviewed in REFS 11,12).
One important in vivo function that is consistent
with these findings is a role of WRN in homology-
dependent recombination repair (HDR). HDR can be
used to repair DNA damage while suppressing gene
loss or rearrangement25,26 (FIG. 1). WRN seems to have
a role late in HDR when recombinant molecules are
topologically disentangled for segregation to daughter
cells (that is, the postsynaptic or resolution phase of
HDR). WRN function during recovery from replica-
tion arrest has also been postulated, largely on the basis
of the functions of the budding and fission yeast RecQ
homologues (see, for example, REF. 27). In mammalian
cells, WRN seems to repair DNA-strand breaks that
arise from replication arrest, and therefore functions to
limit genetic instability and cell death. This is consistent
with the role of WRN in HDR25,26,28.
WRN also has an important role in the maintenance
of telomere length and the suppression of telomere
sister-chromatid exchanges (T-SCEs)29–33. The most
likely explanation for the role of WRN in telomere
maintenance is in the nature of telomeres. Telomeres
are highly structured, G-rich DNA sequences that need
to be partially disassembled to allow DNA replication
and repair. A failure to fully replicate and reassemble
telo meres at the end of S phase might lead to the gener-
ation of telomeric DNA ends that can be recognized
as persistent DNA double-strand breaks to initiate a
damage response that can trigger cellular senescence.
Accurate telomere metabolism is also important to sup-
press genetic instability and chromosome rearrange-
ments34. The catalytic activities of WRN could therefore
be required to make telomeres accessible for replication
and/or repair, or to insure the successful completion of
these processes to restore telomere structure. Common
substrates for WRN function at telomeres and in HDR
might include 3-stranded, forked D- or T-loops, which
are the preferred in vitro substrates for WRN35 (reviewed
in REFS 11,12). Studies in human fibroblasts and in mouse
models of WS (see below) indicate that short telomeres
might trigger a requirement for WRN function30–33,36.
These experiments also indicate that WRN function
at telomeres might require only the helicase activity of
WRN, in contrast to HDR, for which both the helicase
and exonuclease activities of WRN are required16,32,33,37.
Various other nucleic-acid metabolic functions,
including roles in non-homologous DNA-end joining,
base-excision repair, DNA-damage signalling and trans-
cription, have been proposed for WRN (reviewed in
REFS 11,12,38). Although plausible, none of these claims
is yet as well documented or appears to be quantitatively
as important as the roles of WRN in HDR and telomere
maintenance. These two functional roles for WRN (FIG. 1)
are supported by concordant biochemical, cellular,
genetic, patient and/or animal-modelling data.
Mechanistic origins of the WS phenotype
The identification of a role for WRN in HDR and in
telomere maintenance indicates a model for how loss-
of-function mutations might lead to the molecular and
cellular abnormalities observed in WS (FIG. 1). WRN is
proposed to function on DNA substrates that are gener-
ated during HDR repair, the stabilization or repair of
replication forks, or from telomere replication, repair or
remodelling. Successful resolution of these substrates
suppresses genomic instability and maintains telomere
Figure 1 | WRN function and disease pathogenesis. a | WRN has well documented
roles in homology-dependent recombinational repair (HDR) and in telomere
maintenance. These roles might be functionally related; for example, WRN-dependent
maintenance or recombinational repair of telomeres might ensure high cell viability and
genetic stability (WRN+). In the absence of WRN (WRN– ), HDR or telomere processing
can fail, leading to mitotic arrest, cell death or genetic instability. Experimental tests of
this model are shown by the ovals: wild-type WRN re-expression (+wt WRN) improves
both cell survival and the recovery of viable mitotic recombinants, as does expression of
the bacterial resolvase protein RusA (+RusA)25,26. WRN is likely to have a role in several
other nucleic-acid metabolic and repair pathways and in HDR and telomere
maintenance (see text for discussion). b | Model of Werner syndrome (WS) disease
pathogenesis. WRN loss leads to genetic instability, mutation accumulation and cell loss
during and after development in virtually all cell lineages to promote atrophic and/or
progeroid changes and the emergence of neoplastic disease.
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A DNA-repair pathway that
selectively identifies and
replaces single DNA bases that
have been chemically
Mesenchymal cell lineage
Cell lineages that are derived
from the mesodermal germ
layer. Includes many cell types
that are found in connective
tissue and other supporting,
conducting or blood-forming
lineages of the body.
length and structure to ensure high cell viability. In the
absence of WRN function, cells accumulate potentially
toxic DNA intermediates or critically short telomeres
that can trigger genetic instability, DNA damage and
apoptotic response pathways33,36,39. In this model, WS
pathogenesis is driven by defective DNA metabolism
that leads to genetic instability and mutagenesis. These
consequences, together with mutation accumulation and
cell loss, might drive the development of cell type, cell
lineage or tissue-specific defects (FIG. 1). Compromised
tissue or organ structure and function then leads to
two seemingly divergent outcomes: senescence and
mutation-dependent neoplastic proliferation38,40.
Fibroblasts and other mesenchymal cell lineages might
be selectively affected by the loss of WRN function
because of their ability to divide throughout life and their
comparative resistance to DNA-damage-induced apop-
tosis. Moreover, connective tissue lacks the type of com-
partmentalized architecture found in cell lineages such as
epithelia that functions to suppress damage- or mutation-
driven hyperproliferation or neoplasia41. Therefore,
the pathogenesis of WS might reflect the progressive
accumulation of mutant or senescent cells that have lost
cell-specific functions, as well as trophic or regulatory
interactions with adjacent epithelial or stromal cells42.
This model of WS pathogenesis emphasizes the impor-
tance of DNA damage and the progressive accumulation
of cellular defects over time as critical determinants of
WS and associated-disease pathogenesis. This model
of WS pathogenesis also hints at ways in which to limit or
prevent WS complications (BOX 2).
Insights from animal models of WS. Animal models
of WS have been developed to provide a way to better
understand WRN function and WS pathogenesis. So far,
three different WS mouse models have been developed:
a complete Wrn knockout43, an in-frame deletion of the
helicase domain (which leads to a truncated protein that
retains exonuclease activity 44) and transgenic expression
of a human Lys577Met WRN variant protein that lacks
helicase activity in a background of normal murine
Of these three models, only the null mutant of Wrn
recapitulates the biochemical defects that are observed
in WS patients. Although the phenotype of the Wrn-
knockout mouse model remains to be fully characterized,
these animals do not exhibit obvious premature ageing or
a spontaneous cancer predisposition. One way to further
explore the Wrn-knockout phenotype would be to system-
atically challenge these mice with the different types of
DNA damage that selectively kill human WS cells (see
above). A second route to develop more useful mouse
models of WS is to generate sensitized mouse genetic
backgrounds to introduce extra stress on replication,
HDR or telomere-maintenance pathways. For instance,
two groups crossed a murine telomerase-RNA-template-
deficient (or Terc-deficient) mouse with a Wrn-knockout
mouse30. Telomerase deficiency alone leads to progressive
degenerative changes in proliferating tissues such as skin,
gut and bone marrow. In Wrn–/– Terc–/– mice, both groups
observed greying and loss of hair, osteoporosis, diabetes
mellitus and cataracts that increased in severity in later
generations and were correlated with telomeric DNA loss.
Of note, laboratory mouse strains generally have longer
telomeres than do wild-type mice or humans. These
changes therefore depend on critically short telomeres
that arise only after several generations of breeding in the
absence of Terc30,31. A requirement for Wrn deficiency in
conjunction with short telomeres to reveal a phenotype
in Wrn-knockout mice provides an explanation for the
variable and progressive appearance of the phenotype in
different animals. These results are encouraging as they
begin to identify mouse models in which to investigate Wrn
function, and they highlight telomeres as an important
in vivo substrate for Wrn function.
HGPS and A-type lamins
HGPS is the most severe of the progeroid syndromes;
affected individuals have a mean lifespan of 13 years46.
This disease was first described in 1886 (REF. 47), and
is rare: there are currently fewer than 150 documented
cases of HGPS worldwide. HGPS patients gener-
ally appear normal at birth, but prematurely develop
Box 2 | Therapeutic approaches for WS and HGPS
Werner syndrome (WS)
The two avenues that are being explored as therapeutic approaches to WS are
suppression of the biochemical and cellular consequences of WRN loss at the cell level,
and cell replacement to suppress the consequences of WRN loss at the tissue or
organismal level. The most promising candidate for an intervention at the biochemical
level stems from the observation that inhibitors of the mitogen-activated protein
kinase (MAPK) p38, such as SB203580, can suppress the growth and senescence
defects of WRN-deficient fibroblasts in culture97. This work indicates that a stress-
induced, kinase-dependent, telomere-length-independent senescence mechanism
might be operative in fibroblasts from patients with WS. This pathway is a target for
pharmacological suppression that could be further explored in cell-culture models and
in Wrn-knockout mice.
The second, more speculative, strategy is to suppress WS tissue or organismal
phenotypes by attempting to compensate for defects in cell number or cell function.
This could be done by direct transplantation, by stimulating regenerative capacity in
affected tissues or organs (for example, by pharmacological inhibition of p16INK4a98)
or by identifying how tissue-level trophic or regulatory interactions are mediated and
altered in WS (see, for example, REFS 42,99). All three of these tissue-level approaches
will require a better understanding of normal biology and WS pathogenesis, and
therefore would greatly benefit from improved WS mouse models.
Hutchinson–Gilford progeria syndrome (HGPS)
Farnesyltransferase inhibitors (FTIs) represent a promising way to treat HGPS owing to
their ability to block farnesylation of progerin and an ability to suppress development of
the HGPS phenotype in mouse models. These drugs are also safe for clinical use.
However, treating patients with FTIs, does not eliminate expression of progerin and
prelamin A, but rather causes these proteins to accumulate in their unfarnesylated forms.
Also at issue is whether the beneficial effects of FTIs are direct or secondary, because FTI
treatment of HGPS-model mice results in an incomplete blockade of prelamin A
maturation72. Therefore, significant levels of farnesylated progerin likely remain, and FTIs
might function either through partial inhibition of progerin farnesylation or through
effects on another CAAX-containing protein. Furthermore, although most cases of HGPS
are associated with progerin expression, several HGPS-associated alleles have been
identified that are not predicted to alter lamin A processing48,50,51,100,101. The potential
efficacy of FTIs in such instances remains in question, although they might be expected
to interfere with the transient prenylation of mutant proteins and target them away from
the nuclear periphery, which might suppress toxicity. It would therefore be useful to
determine the ability of FTIs to rescue defects in nuclear organization across the
spectrum of laminopathy mutations.
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The proteinacious meshwork
that underlies the inner nuclear
several features that are associated with ageing, includ-
ing alopecia, atherosclerosis, rapid loss of joint mobility,
osteolysis, severe lipodystrophy, scleroderma and varied
skin hyperpigmentation. Death in patients with HGPS
frequently results from stroke or coronary failure.
HGPS patients might also have developmental defects
of the clavicle, mandible and cranium as well as marked
growth retardation (an extensive description of the
HGPS phenotype can be found in REF. 46). The genetic
basis of HGPS was uncovered in 2003, when it was found
that most cases of the disease are associated with a single-
nucleotide substitution that leads to aberrant splicing
of LMNA, the gene that encodes the A-type nuclear
lamins48–50. In most instances, HGPS is associated with
dominant, de novo germline mutations. However, in
some instances the disease seems to result from com-
pounded heterozygous mutations or homozygous point
All A-type lamins, of which the most abundant are
lamins A and C (hereafter lamin A/C), are encoded
by a single LMNA locus through alternative splicing52.
A-type lamins belong to the family of intermediate-
filament proteins that, along with the B-type lamins,
are the main constituents of the nuclear lamina in most
differentiated cells. The ability of lamins to multi merize
into filaments lends both rigidity and elasticity to the
nuclear lamina53. Although the A-types lamins are
highly enriched at the nuclear periphery, they can also
be detected at discrete sites in the nucleus, where they
might perform specific functions linked to cell pro-
liferation54,55. In addition to maintaining the integrity
and shape of the nuclear envelope, lamin A/C has been
implicated in the regulation of transcription, DNA
replication, cell-cycle control and cellular differentia-
tion56–59. The involvement of A-type lamins in so many
diverse cellular processes is likely to depend on both
direct interactions of lamin A/C with nuclear proteins
and chromatin, as well as their role in establishing a
nuclear environment that is conducive to various
nucleic-acid metabolic and signalling processes.
LMNA and laminopathies. The identification of LMNA
as the gene responsible for HGPS puts this disease into
a broader category of laminopathies, which includes at
least ten distinct diseases, each caused by mutations in
LMNA60. These diseases include forms of muscular dys-
trophy and cardiomyopathy, a rare familial lipo dystrophy,
Charcot–Marie–Tooth syndrome, and several other
diseases with progeroid features (described in detail
below). In most instances, the laminopathies are asso-
ciated with dominant missense mutations in LMNA. In
total, over 200 disease-associated mutations in LMNA
have been reported (see Leiden Muscular Dystrophy
pages and The LMNA mutation database in Further
information). It is not known why one LMNA point
mutation can lead to one disease, whereas another
nearby point mutation can lead to a different pheno-
type and disease. The phenotype of the Lmna-knockout
mouse61–63 indicates that mutations that lead to loss of
lamin A/C function result in muscular dystrophy, dilated
cardio myopathy and possibly Charcot–Marie–Tooth
syndrome, whereas other diseases such as HGPS might
result from mutations that lead to elevated or novel
activities of lamin A/C.
Among the laminopathies, three might be related to
HGPS at both the phenotypic and molecular level. For
example, four patients diagnosed with so-called atypical
WS were found to carry point mutations in LMNA, which
indicated that these patients might be afflicted with a less
severe form of HGPS64. All of the LMNA mutations that
are associated with atypical WS map to the N-terminal
end of the rod domain (BOX 3), where at least one HGPS-
associated mutation has also been mapped48. By contrast,
most of HGPS mutations map close to the C-terminal
processing site of the lamin A protein. One possibility
is that mutations at the N terminus of lamin A confer
a similar, although potentially milder, toxicity to that
which results from mutations proximal to the prelamin
A processing site.
Mandibuloacral dysplasia (MAD) and restrictive
dermopathy (RD) appear to be clinically mild and
severe variants, respectively, of an HGPS-like pheno-
type. Both diseases can result from mutations in either
LMNA or in ZMPSTE24, which encodes a protease that
is required for the maturation of lamin A (see below).
Along with patients with HGPS, patients with MAD
and RD have some degree of progeroid features, and
the underlying molecular mechanisms of the disease in
each case seems to depend at least in part on defective
lamin A maturation.
Altering lamin A processing
The lamin A protein is synthesized as a 664-amino-acid
precursor protein, called prelamin A (reviewed in REF. 65).
Prelamin A contains a C-terminal CAAX amino-acid
motif that undergoes farnesylation at the Cys residue.
Farnesylated prelamin A undergoes two cleavages; the first
takes place C-terminal to the modified Cys, whereas the
second removes 15 C-terminal residues, including
the farnesyl–Cys. The mature lamin A protein contains no
farnesyl modification (FIG. 2). Deletion of the endopepti-
dase-encoding gene Zmpste24 blocks both prelamin A
cleavage events and the production of mature lamin A.
The resulting protein that accumulates is farnesylated,
uncleaved prelamin A66. Due to differential splicing of the
exons that encode the C terminus, lamin C is synthesized
without the CAAX motif, and therefore does not undergo
The most frequent HGPS-associated mutation,
Gly608Gly, is a silent base substitution that activates a
cryptic splice donor in exon 11 of LMNA (BOX 3). Use of
this anomalous splice donor leads to the loss of 150 nucleo-
tides from the 3′ end of exon 11 in the mature lamin A
mRNA, and internal deletion of 50 amino-acid residues
from the C terminus of lamin A. The resulting mutant
protein is called progerin. Progerin retains its C-terminal
CAAX motif, and therefore is farnesylated. However, it
lacks the recognition site for the second cleavage event
and it therefore accumulates in farnesylated form, which
localizes exclusively to the nuclear periphery67 owing to
the association of the hydrophobic prenyl group of the
protein with the nuclear envelope.
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© 2007 Nature Publishing Group
∆35 Lamin A
∆50 Lamin A/progerin
∆90 Lamin A
Atypical Werner syndrome
Other progeria-like syndromes
Hutchinson–Gilford progeria syndrome
C O CH3
∆ ∆50 Lamin A/
headNLS C-terminal tail
Coiled-coil rod domain
123456789 10 1112
Cells from patients with HGPS display several pheno-
types that indicate that their general nuclear organization
and dynamics are compromised. For example, cells from
patients with HGPS display irregular nuclear morphology,
a phenotype that has been considered diagnostic of
HGPS48,49 and consistent with altered lamin A/C func-
tion. However, cells from patients with most, if not all,
of the other laminopathies also exhibit this phenotype.
Cells from patients with HGPS also show relocalization
or decreased expression of the heterochromatin marker
heterochromatin protein-1 (HP1) and of members
of the lamina-associated polypeptide-2 (LAP2) family of
proteins68, altered patterns of histone modification and
evidence of DNA damage69. Similar cellular phenotypes
have been observed in fibroblasts that have undergone
physiological ageing in vivo or that have been continuously
passaged in vitro70.
Interfering with lamin A processing in the mouse,
either by deleting Zmpste24 or by expressing progerin,
results in an HGPS-like phenotype66,71,72. Treating these
mice with farnesyltransferase inhibitors (FTIs) markedly
ameliorates many of the HGPS-like phenotypes such as
lack of adipose tissue, growth retardation and skeletal
pathology72–74 (BOX 2). FTI treatment is also correlated
Box 3 | Progeria-associated LMNA mutations
In addition to Hutchinson–Gilford progeria syndrome (HGPS), several other progeria-like syndromes, including atypical
Werner syndrome (WS), mandibuloacral dysplasia (MAD) and restrictive dermopathy (RD), are also associated with
mutations in LMNA or ZMPSTE24 (REFS 102–105). Known progeria-associated mutations are shown against the exon
structure of human LMNA (panel a). Mutations such Arg471Cys and Arg527Cys50 were identified in individuals who are
compound heterozygous for these alleles.
MAD, like HGPS, features lipodystrophy, alopecia and short stature as well as developmental defects of the mandible
and clavicle, and a mild progeroid appearance, and might represent a mild form of HGPS. MAD can result from
homozygous mutation in LMNA or compound heterozygous mutation in ZMPSTE24 (REFS 102,103,105). By contrast,
RD might be an exaggerated form of HGPS. RD is a perinatally lethal disease with marked dermal hypoplasia, abnormal
epidermal structure and joint contractures. In most cases, cells from RD fetuses are devoid of ZMPSTE24 activity owing to
nonsense mutations in both copies of ZMPSTE24 (REF. 106), and therefore they fail to process prelamin A. So, prelamin A
processing is central to the pathogenesis of MAD, HGPS and RD. These syndromes, therefore, might represent a
continuum of increasingly severe, mechanistically related phenotypes.
The most common HGPS-associated mutation, Gly608Gly, causes 150 nucleotides encoded in exon 11 to be spliced out
of the final mRNA and results in a protein that lacks 50 amino acids (panel b). This protein, progerin, retains its C-terminal
CAAX motif but lacks sequences that are required for complete processing and is, therefore, stably farnesylated. Similarly,
RD can result from heterozygous mutations altering the splicing of exon 11 of LMNA104, and in one case this causes the
complete removal of exon 11 and produces a protein that is similar to progerin but that lacks 90 amino acids at the
C terminus. By contrast, a similar but smaller C-terminal deletion (35 amino acids) has been identified in a patient with
HGPS who survived more than 30 years longer than the average disease-associated life expectancy107. In this case, the
causative LMNA mutation activated a cryptic splice donor 3′ to the site that leads to progerin production from the
Gly608Gly allele. This succession of progerin-like deletions, removing 35, 50 and 90 amino acids in, mild HGPS, canonical
HGPS and RD, respectively, seems to represent an allelic series of increasing toxicity. However, the effect of each of these
deletions on lamin A function is unclear. NLS, nuclear-localization signal.
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headNLS C-terminal tail
Coiled-coil rod domain
C O CH3
C O CH3
An allele of a gene that confers
to the encoded gene product a
new activity not normally
found in the product encoded
by the wild-type allele.
An allele of a gene that confers
to the encoded gene product
an increase in the activity that
is normally associated with the
product encoded by the wild-
with the relocalization of the lamin A protein away from
the nuclear periphery and partially rescues the nuclear
morphology phenotype73,75–78. These data strongly
indicate that stably farnesylated lamin A at the nuclear
periphery is toxic owing to elevated or novel lamin A
function at this subnuclear location. This is consistent
with the dominant inheritance of HGPS.
Mechanistic origins of the HGPS phenotype
How does expression of progerin lead to HGPS? The
genetics of HGPS strongly indicate that HGPS-associated
mutations are dominant neomorphic or hypermorphic alleles
of LMNA. By contrast, as noted above, deletion of Lmna
in the mouse results in a muscular dystrophy phenotype
that is distinct from the phenotype that results from the
expression of progerin. On the basis of FTI data, stable
farnesylation of progerin also seems to be associated with
the pathogenesis of HGPS. This hypothesis is further
supported by the finding that deletion of Zmpste24, the
endopeptidase that is responsible for both prelamin A
cleavage events, results in an HGPS-like phenotype in
the mouse66,71. Despite these observations, it is unlikely
that stable farnesylation of progerin alone accounts for its
toxicity. As noted above, several HGPS-associated muta-
tions are not predicted to alter prelamin A processing.
Moreover, in some assays progerin behaves differently
from lamin A mutants that are stably prenylated owing
to site-directed mutation of the cleavage sites59.
Several reports have indicated that progerin alters the
composition and mechanical properties of the nuclear
lamina. HGPS cells in culture show age- and passage-
dependent changes in nuclear morphology that are cor-
related with increasing levels of progerin79. One potential
explanation for these changes in morphology is altered
interaction between A- and B-type lamins. Fluorescence
resonance energy transfer (FRET) analyses have demon-
strated that although A- and B-type lamins can interact
in vitro, they segregate into distinct homopolymers
in vivo80. Progerin disrupts this segregation, possibly
because its high affinity for the nuclear envelope causes
it to juxtapose more tightly to the membrane, a location
normally solely occupied by constitutively prenylated
Figure 2 | The maturation of lamin A. Lamin A is synthesized as the 664-amino-acid precursor protein prelamin A.
Prelamin A contains a C-terminal CAAX motif that directs farnesylation by farnesyl protein transferase. This step can be
blocked by farnesyltransferase inhibitors (FTIs), which inhibit all subsequent processing reactions. Following farnesylation,
the three C-terminal amino acids of prelamin A are cleaved and the new C terminus is methylated. This cleavage event
requires the endopeptidase ZMPSTE24. Subsequently, the maturing lamin A molecule rapidly undergoes a second
cleavage event, also mediated by ZMPSTE24, removing the 15 C-terminal residues, including the farnesylated Cys residue.
This process results in mature lamin A that contains no farnesyl modification. Like other intermediate-filament proteins,
lamin A contains N- and C-terminal globular domains that flank a coiled-coil rod domain. This central rod domain
mediates the protein–protein interaction between lamin A molecules that allows for filament formation. The nuclear
localization of lamin A is driven by a nuclear-localization signal (NLS) that is adjacent to the C-terminal globular domain.
400 | MAY 2007 | VOLUME 8
© 2007 Nature Publishing Group
B-type lamins. Biochemical fractionation and live-cell
imaging experiments have also shown that progerin
expression induces immobilization of A-type lamins
in the nuclear lamina67. This is correlated with distinct
changes in the mechanical properties of progerin-
expressing cells that differ from Lmna–/– cells. How
these changes in nuclear structure and dynamics lead
to HGPS is unclear, although one intriguing and test-
able hypothesis is that these progerin-dependent defects
trigger a structural checkpoint that suppresses both cell
proliferation and survival.
An activated DNA-damage response. Cells derived from
patients with HGPS and HGPS mouse models display
several indicators of an activated DNA-damage response,
including enhanced phosphorylation of histone H2AX
and markedly increased transcription of p53 target
genes69,81. Cells from patients with HPGS might also dis-
play aneuploidy and chromosome instability. These cells
show delayed recruitment of DNA-repair proteins to sites
of DNA damage, sensitivity to double-strand breaks and
reduced cell proliferation. That these cellular phenotypes
are causally linked to the HGPS phenotype is suggested
by evidence that deletion of p53 in the Zmpste24–/– mouse
model of HGPS partially mitigates some of the progeroid
phenotypes and extends lifespan81. Although tantalizing,
the cohort size of the Zmpste24–/– p53–/– mice in this
study was limited and further studies of the relationship
between progerin and p53 are warranted. It is unknown
how progerin causes these phenotypes, although these
observations are consistent with the idea that progerin
interferes with DNA repair while permitting damage
detection and signalling through p53. This could constitute
a positive-feedback loop, leading to the accumulation of
DNA damage over time and constitutive activation of a
damage response. These observations identify the role of
lamin A in DNA repair and the DNA-damage response
as important areas for further research.
Ultimately, changes in the function of the nuclear lamina
that result from the expression of progerin must cause
changes in cellular viability, function and gene expres-
sion. Characterization of cells from patients with HGPS
in culture has revealed decreased proliferative capac-
ity82 and several changes in gene expression, especially
of extracellular matrix proteins83–85. It remains unclear
how directly these changes result from progerin expres-
sion. For example, the altered mechanical properties of
HGPS nuclei probably result directly from the ability
of progerin to interfere with the composition of the
nuclear lamina. Similarly, the DNA-repair defects and
altered gene-expression patterns in HGPS cells might
result from the direct interference of progerin with the
protein complexes that are involved in these processes.
Alternatively, the faulty nuclear structure imparted by
progerin might be responsible for defective targeting
of repair complexes to damage sites or of transcrip-
tion factors to their sites of activity. Furthermore, the
altered dynamics of the nuclei might result in changes
in mechano sensitive gene expression86. Each of these
changes has the potential to disrupt the proliferative
capacity, viability and function of cells, and taken together
all these perturbations might contribute to the progeroid
features that are characteristic of HGPS (FIG. 3).
Insights from mouse models of HGPS. Several murine
models of HGPS have been developed, providing insight
into disease mechanisms and a way to test the efficacy of
potential therapies. The development of the first HGPS-
like mouse model was largely serendipitous: Mounkes et al.
generated a mouse in which the Lmna gene had been
altered to express a muscular-dystrophy-associated Lmna
allele87. However, they were surprised to find a mouse
that developed severe HGPS-like phenotypes, including
growth retardation, decreased hair-follicle density, and
skin and muscle defects. Analysis of the products derived
from the altered Lmna gene revealed that the targeted
mutation unexpectedly altered Lmna splicing.
More recently, mouse models have been generated
by either transgenic expression of human progerin88 or by
the replacement of a 3′ region of the Lmna gene with a
single exon that encodes the C terminus of progerin73. The
Zmpste24–/– mouse has also been used to model HGPS
in light of its HGPS-like phenotype, which is dependent
on defective lamin A processing and the presence of
functional p53 (REFS 81,89). Whereas the transgenic
HGPS mouse shows phenotypes that are largely restricted
to the vascular system, including progressive loss of
vascular smooth-muscle cells and thickening of the walls
of large vessels, the other two models show a broader
progeria-like phenotype with severe growth retardation,
fragile bones, alopecia, skin defects and dram atically
reduced viability. The phenotype of the HGPS C-terminal
progerin-replacement mouse can be made more severe by
crossing the mutant allele to homozygosity, or by crossing
a single copy of the HGPS allele into a null background.
Of note, both the C-terminal progerin replacement
mouse and the Zmpste24–/– mouse show considerable
phenotypic improvement in growth and survival when
treated with FTIs72,74 (BOX 2).
Figure 3 | Model for the pathogenesis of HGPS in the presence of progerin. Progerin
disrupts the composition and dynamics of the nuclear lamina, which might lead to cell
death or dysfunction. These changes might also generate DNA damage or interfere with
DNA repair in cells from patients with Hutchinson–Gilford progeria syndrome (HGPS),
leading to the accumulation of DNA damage and the constitutive activation of a
p53-dependent checkpoint response. Similarly, changes in gene expression might
contribute to the overall HGPS cellular phenotype. Cell dysfunction, proliferative
defects and cell death that result from progerin expression contribute to generate the
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Progeroid syndromes and normal ageing
The striking, progressive phenotypes of WS and of
HGPS have suggested that one or both syndromes
might represent a form of premature or accelerated
ageing that is mechanistically linked to normal ageing.
However, careful clinical and pathological examination
of patients with either WS or HGPS has pointed out
differences in the nature or degree of changes between
patients and normally aged individuals. For example,
WS is commonly referred to as a premature-ageing
syndrome despite both quantitative and qualitative
differences with normal ageing, including the greater
extent or severity of the loss of hair or hair colour and
the development of an unusual type of ocular cataract or
unusual neoplasms4. These differences led Epstein and
colleagues to conclude that WS was neither precocious
nor accelerated ageing, but “may be better considered a
‘caricature’ of aging, exaggerating, although not neces-
sarily by the same mechanisms, some of the clinical and
pathologic changes which connote aging4.”
If this conclusion is correct, how likely is it that the
knowledge gained studying WS or HGPS will provide
general insights into the biology of ageing or the patho-
genesis of age-associated disease? One view is that
progeroid syndromes represent phenocopies of what we
are really interested in: the mechanisms that underlie
normal ageing or disease pathogenesis90. Therefore the
underlying biology of WS or HGPS might be fascin-
ating in its own right, but unlikely to reveal broader
mechanistic aspects of ageing or disease pathogenesis.
A more optimistic view, to which we subscribe, is that
many progeroid syndromes might have partial mecha-
nistic overlap with normal ageing and therefore might
provide uniquely informative opportunities to formulate
and test hypotheses regarding the biology of ageing and
How can we identify mechanistic links? Three different
avenues of research might aid the identification of mecha-
nistic links between the progeroid syndromes and normal
ageing or disease pathogenesis. These links include
better definition of the underlying normal biology,
the use of genetic and environmental modifiers to
confirm suspected links and establish causation, and
the linkage of cellular changes to tissue or organismal
For example, there is considerable interest in the role
of DNA damage and altered DNA-damage responses
as mediators of ageing and age-associated disease. This
notion is further supported by the characterization of
a number of other human and animal mutations that
result in progeroid features60. The mutated genes in these
instances have been associated with various functions,
among which the most common is DNA metabolism. Two
recent reports92,93 describe the analyses of DNA-repair-
deficient patients and mice that provide new information
on this question, and identify a common mechanism
by which exogenous and endogenous DNA damage
might trigger the development of progeroid changes.
This mechanism entails DNA-damage-dependent
suppression of growth hormone (GH)–insulin-like
growth-factor-1 (IGF1) somatotroph signalling, a deeply
conserved, important regulator of metabolism and
longevity in many organisms94. Therefore, it would be
useful to know whether lamin A/C function and WRN
function converge on DNA repair and the response to
DNA damage, what roles they have in these processes,
and how these roles are modified or disrupted by WS- or
A second strategy focuses on in vivo analyses of
cellular phenotypes that accompany disease-associated
mutations in WRN and LMNA. There are now a growing
number of morphological and molecular tools to iden-
tify and quantify persistent DNA-damage signalling, cell
death and cellular senescence in tissue. The application
of these tools to patients and to animal models should
give us a better sense of the extent to which impaired cell
proliferation, excessive cell death or the accumulation of
senescent cells contribute to the pathogenesis of WS and
HGPS. It will also be important to determine whether
these cellular changes are selectively targeted to specific
cell lineages or tissues.
A converse strategy to analyse progeroid syndromes
has been to search for genes or pathways that delay age-
ing or extend lifespan when they are mutated. These
longevity mutations have been proposed to be enriched
in genes that modulate normal ageing95. It is of interest
to note that the genes and pathways identified so far by
these two mutation-driven approaches show little over-
lap. To this end, efforts are underway to identify WRN
and LMNA polymorphisms that are associated with
Recently, a potential link between LMNA and cellular
senescence was reported. Human cells with normal
LMNA genes were found to produce small amounts of
progerin protein by using the same splice sites that are
used by HGPS-associated LMNA alleles70. The ability of
morpholino oligonucleotide-mediated ablation of pro-
gerin production to reverse some of the nuclear struc-
tural defects associated with cellular ageing indicates
that progerin expression might have a role in normal
cell senescence. If endogenous progerin production also
promotes cellular senescence in the mouse, it might be
possible to extend lifespan by engineering the Lmna
locus to block progerin production. This would establish
a strong mechanistic link between the pathogenesis of
HGPS and normal ageing.
The ‘greying’ of many human populations has provided
a strong stimulus to better understand ageing and the
pathogenesis of age-related disease. New knowledge will
have considerable practical, as well as conceptual, impor-
tance. Recent progress to understand the molecular basis
of WS and HGPS, two well characterized, genetically
defined human progeroid syndromes, has led to the sug-
gestion that different primary nuclear metabolic defects
might accelerate ageing. The likely mechanism is by
directly or indirectly promoting mutation accumulation,
together with persistent activation of DNA-damage-
dependent cell-signalling pathways. The most exciting
consequence of identifying common mechanistic features
402 | MAY 2007 | VOLUME 8
© 2007 Nature Publishing Group
of progeroid syndromes, such as WS or HGPS, and of
normal ageing or age-associated disease pathways is the
prospect of identifying new ways to improve quality of
life and to treat or prevent age-associated disease.
Note added in proof
Two recent papers by Cao et al.108 and Dechat et al.109
demonstrate that the constitutive farnesylation of pro-
gerin causes it to associate with membrane structures
throughout the cell cycle, even in mitosis when lamin A
normally becomes soluble. The mitotic membrane asso-
ciation of progerin is akin to that of the B-type lamins.
Cells expressing progerin appear to have delayed and
defective mitotic progression, suggesting that the inap-
propriate association of an A-type lamin with mitotic
membrane structures interferes with some processes
in mitosis. How these findings relate to the progeroid
phenotype of HGPS remains to be elucidated.
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B.A.K. was supported in part by a National Institute of
General Medical Science grant. Lamin-related research in
the laboratory of B.K.K. is supported by a National Institutes
of Health grant. This work was supported by grants from
National Cancer Institute and the Nippon Boehringer
Ingelheim Virtual Research Institute on Aging to R.J.M.Jr.
Competing interests statement
The authors declare no competing financial interests.
The following terms in this article are linked online to:
LMNA | WRN | ZMPSTE24
Ataxia-telangiectasia | Down syndrome | Hutchinson–Gilford
progeria syndrome | Werner syndrome
Ray Monnat’s laboratory:
Leiden Muscular Dystrophy pages:
Locus-Specific Mutational Database: http://www.pathology.
Online Mendelian Inheritance in Man: http://www.ncbi.nlm.
SNP linked to WRN: http://www.ncbi.nlm.nih.gov/SNP/snp_
The LMNA mutation database: http://www.umd.be:2000
Werner Syndrome International Registry: http://www.
Access to this links box is available online.
404 | MAY 2007 | VOLUME 8
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