Download Genotype–phenotype correlations in laminopathies

Nuclear Envelope Disease and Chromatin Organization 2009
Genotype–phenotype correlations in
laminopathies: how does fate translate?
Juergen Scharner, Viola F. Gnocchi, Juliet A. Ellis1 and Peter S. Zammit1
King’s College London, Randall Division of Cell and Molecular Biophysics, New Hunt’s House, Guy’s Campus, London SE1 1UL, U.K.
Abstract
A-type laminopathies are a group of diseases resulting from mutations in the intermediate filament
proteins lamin A and C (both encoded by the LMNA gene), but for which the pathogenic mechanisms are
little understood. In some laminopathies, there is a good correlation between the presence of a specific
LMNA mutation and the disease diagnosed. In others however, many different mutations can give rise to
the same clinical condition, even though the mutations may be distributed throughout one, or more, of the
three functionally distinct protein domains of lamin A/C. Conversely, certain mutations can cause multiple
laminopathies, with related patients carrying an identical mutation even having separate diseases, often
affecting different tissues. Therefore clarifying genotype–phenotype links may provide important insights
into both disease penetrance and mechanism. In the present paper, we review recent developments in
genotype–phenotype correlations in laminopathies and discuss the factors that could influence pathology.
Introduction
Mutations in the LMNA gene cause a variety of diseases
collectively called ‘laminopathies’. To date, more than
340 unique LMNA mutations (http://www.umd.be) [1]
are known that cause 16 different diseases including
A-EDMD
(autosomal
Emery–Dreifuss
muscular
dystrophy), DCM (dilated cardiomyopathy), LGMD1B
(limb-girdle muscular dystrophy 1B), L-CMD (LMNArelated congenital muscular dystrophy), FPLD2 (familial
partial lipodystrophy 2), HGPS (Hutchinson–Gilford
progeria syndrome), atypical WRN (Werner syndrome),
MAD (mandibuloacral dysplasia) and CMT2B (Charcot–
Marie–Tooth disorder type 2B).
The LMNA gene is alternatively spliced to produce the
type V intermediate filament proteins lamin A, C, C2 and
del10. Together with B-type lamins, lamin A and C are the
major components of the nuclear lamina (a fibrous proteinaceous meshwork underlying the nuclear envelope). The nuclear lamina functions to maintain both nuclear and cellular architecture and plays a role in chromatin organization and gene
expression [2]. The presence of mutant forms of lamin A/C is
thought to perturb some, or all, of these functions of the nuclear lamina, but it is generally unclear how specific mutations
result in a particular laminopathy. Phenotypic clustering, the
Key words: autosomal Emery–Dreifuss muscular dystrophy (A-EDMD), dilated cardiomyopathy
(DCM), familial partial lipodystrophy 2 (FPLD2), Hutchinson–Gilford progeria syndrome (HGPS),
lamin, laminopathy, LMNA, limb-girdle muscular dystrophy 1B (LGMD1B).
Abbreviations used: A-EDMD, autosomal Emery–Dreifuss muscular dystrophy; CMT2B, Charcot–
Marie–Tooth disorder type 2B; DCM, dilated cardiomyopathy; FPLD2, familial partial lipodystrophy
2; HGPS, Hutchinson–Gilford progeria syndrome; L-CMD, LMNA-related congenital muscular
dystrophy; LGMD1B, limb-girdle muscular dystrophy 1B; MAD, mandibuloacral dysplasia; SNP,
single nucleotide polymorphism; SREBP, sterol-regulatory-element-binding protein; WRN, Werner
syndrome.
1
Correspondence may be addressed to either of these authors (email [email protected]
or [email protected]).
Biochem. Soc. Trans. (2010) 38, 257–262; doi:10.1042/BST0380257
systematic correlation of phenotype with genotype, is becoming increasingly important to understand underlying mechanisms of monogenic diseases [3–5]. Here, we review the correlation of LMNA mutation with clinical diagnosis, to explore
genotype–phenotype links within laminopathies (Figure 1).
Laminopathies with a more consistent
genotype–phenotype link
To date, mutations distributed throughout the gene and
affecting almost 20% of the coding sequence of LMNA have
been reported from more than 1000 patients, and arise mainly
from missense or frameshift mutations (http://www.umd.be)
[1]. In some laminopathies such as HGPS, ‘hot-spot’ or
founder mutations result in a similar phenotype. HGPS
is almost always caused by the de novo base mutation
c.1824C>T/p.G608G, which results in a cryptic splice donor
site in the lamin A-specific exon 11, and deletion of the
remaining 50 amino acids of the C-terminus [6]. The resulting
truncated protein (termed progerin) retains the CAAX box
but lacks the endoproteolytic cleavage site, so it cannot
be processed by Zmpste24, and is incorporated into the
nuclear lamina carrying the C-terminal farnesyl group. Two
unrelated patients with severe forms of HGPS have recently
been reported carrying two new mutations (c.1968+1G>A
and c.1821G>A), but both cause a frequent use of the splice
donor site that is activated in typical HGPS patients [7].
Other laminopathies also appear to arise from a common
LMNA mutation, such as WRN (R133L), CMT2B (R298C)
and MAD (R527H) (although R133L also causes FPLD2, and
R527H additionally results in A-EDMD) (Figure 1) [8].
Although the number of patients developing HGPS, WRN,
CMT2B or MAD is small, it is likely that the presence of
a particular mutation will have a predictive value on the
C The
C 2010 Biochemical Society
Authors Journal compilation 257
258
Biochemical Society Transactions (2010) Volume 38, part 1
Figure 1 Distribution of lamin A mutations and their related laminopathies
(a) Schematic diagram of the LMNA gene, with exons encoding their respective protein domains colour coded and the lamin
A splice site indicated in red above. HGPS mutations causing a new splice donor site are indicated in black boxes. (b) The
lamin A protein with mutations indicated that result in A-EDMD (blue), DCM (green), LGMD1B (black), L-CMD (gold), FPLD2
(red) and CMT2B (plum). ‘†’ indicates that the same amino acid change causes different laminopathies. *R133L also causes
WRN, *S143F additionally results in HGPS, *R527H causes MAD too and *R644C also gives rise to a range of other disorders
[26–29]. ◦ Patients carrying R527C develop either a severe form of MAD and/or progeria [52,53]. Mutation/laminopathy
correlations are from [1,9]. Interacting proteins and their corresponding binding regions on lamin A are indicated below [54].
clinical diagnosis and that the pathogenic mechanism will be
similar for a given disorder (Figure 2a). Importantly, these
disorders are characterized by systemic effects, with many
tissues affected, unlike the more common laminopathies.
Laminopathies with an inconsistent
genotype–phenotype link
By contrast, laminopathies with striated muscle involvement
(A-EDMD, LGMD1B, L-CMD and DCM), together accounting for ∼60% of all laminopathies, along with those affecting adipose tissue (FPLD2), are caused by a large number
of different mutations (Figure 1). A-EDMD (blue in Figure 1)
and L-CMD (gold in Figure 1) mutations are distributed
throughout the gene, whereas LGMD1B (black in Figure 1)
mutations tend to cluster in both the Ig-like fold and coil 2
[1,9]. DCM (green in Figure 1) patients tend to carry mutations throughout the rod domain and can share clinical characteristics with A-EDMD patients, where an isolated cardiac
involvement has been described. For FPLD2, there is an apparent ‘hot spot’ for mutations in the Ig-like fold where 75%
C The
C 2010 Biochemical Society
Authors Journal compilation of all mutations occur. The remaining 25% are distributed
throughout the protein and are distinct from those causing
A-EDMD (Figure 1). Interestingly, muscle involvement has
not been observed in FPLD2 patients. The C-terminal
domain of lamin A binds SREBP1 (sterol-regulatoryelement-binding protein 1) and SREBP2, which play a key
role in adipocyte differentiation and cholesterol biosynthesis
respectively [10]. Thus certain mutations may disrupt lamin
A–SREBP1/2 interactions to specifically affect adipocyte
function.
Phenotypic clustering using mutation type
Bonne et al. [11] first attempted a genotype–phenotype
correlation by mutation type in LMNA. Of the 53 patients
analysed, all 12 with isolated heart involvement carried
a nonsense mutation in Q6X of the head domain. In
the remaining 41 patients with muscle weakness however,
attempts to correlate disease severity with the protein domain
affected by the missense mutations proved inconclusive. Our
own analysis of LMNA patients (http://www.interfil.org)
Nuclear Envelope Disease and Chromatin Organization 2009
Figure 2 Modes of LMNA genotype–phenotype correlation
(a) A consistent genotype–phenotype correlation indicates a likely common disease mechanism. (b) LMNA mutations distributed throughout
the protein can each cause a particular laminopathy. Some groups of
mutations probably have a common disease mechanism, while other
mutations appear to operate by separate pathways to cause the same
laminopathy. (c) Specific LMNA mutations combined with LMNA SNPs, or
mutations/SNPs in other proteins, act through combined mechanisms to
cause modified phenotypes, such as atypical laminopathies or different
laminopathies in individual patients carrying identical mutations.
the domain surface without affecting structural integrity: with
R482W, for example, not changing the crystal structure of
the mutant protein [13–15]. However, tetrameric aggregates
of mutant molecules were found that did not occur in the
original structure, such that R482W or R482Q might cause an
allosteric effect, allowing the repositioning of the C-terminal
β-strand g , leading to a novel aggregation state and so
possibly contributing to disease [13]. A similar phenomenon
occurs with the F12L mutation in porphobilinogen synthase,
which initiates a transition of the aggregation state, significantly changing the enzyme kinetics [16]. Certain mutations,
therefore, could have a common mechanism to cause a
particular laminopathy, but it is less clear how mutations
located in functionally distinct protein domains could operate
by the same disease mechanism (Figures 1 and 2b).
Differential effects of LMNA mutations in
post-mitotic cells compared with dividing
cells
[1] with frameshift mutations found that 62% (18/29)
developed DCM, again associating DCM with truncated
protein species (J. Scharner, V. Gnocchi, J.A. Ellis and P.S.
Zammit, unpublished work). Benedetti et al. [12] separated
neuromuscular patients according to the age of disease onset.
The type of LMNA mutation differed, such that 89% (17/19)
early-onset patients carried missense mutations and in-frame
deletions, while only 63% (5/8) of late-onset patients did. The
remaining three late-onset patients had frameshift mutations,
presumably resulting in a truncated protein. Interestingly,
variants associated with early onset were primarily found in
the Ig-like fold (35%) and in coil 2A (24%), while variants
associated with late onset mainly occurred in coil 2B (60%)
[12]. These results indicate that the underlying disease mechanism may be associated with the functional properties of the
affected protein domain rather than with the type of mutation.
Structural changes of mutant lamin A in
A-EDMD, but not in FPLD2
Mutations in the Ig-like fold provide evidence of a genotype–
phenotype correlation [13,14]. This globular region in
the C-terminal domain harbours both A-EDMD (e.g.
R453W and R572P) and FPLD2 (e.g. R482W, R482Q and
K486N), causing mutations in close proximity (Figure 1).
Mutations causing laminopathies with striated muscle
involvement occur at positions that play a critical role in
the structural stability of the C-terminal domain. Conversely,
those that lead to FPLD2 result from a lost positive charge on
An LMNA mutation causing A-EDMD (R453W) perturbs
myogenic differentiation, while an FPLD2-causing mutation
(R482W) does not, again suggesting that certain mutations
can have tissue-specific effects [17]. Many LMNA mutations
probably have common effects, including compromised
nuclear integrity and transcriptional regulation, but some
may also have additional actions. Particular mutant lamin
A variants delay cell cycle progression by prolonging
S-phase [18], and some also hinder the exit from cell
cycle and/or the nuclear rearrangements, required for
myogenic differentiation in immortalized cell lines [17,19].
The functional cells of cardiac muscle, skeletal muscle and
adipose tissue are post-mitotic, but skeletal muscle retains
a well-characterized stem cell compartment, responsible for
homoeostatic myonuclear turnover, hypertrophy and repair
[20]. Thus skeletal muscle may additionally be vulnerable
to mutations that also affect cell cycle and/or differentiation
of myogenic stem cells. Such a mutation, therefore, may
not only influence the onset and severity of A-EDMD [21]
or produce L-CMD [9], but even influence which tissue is
affected and so the type of laminopathy caused.
Lamin A or lamin C or both?
Since LMNA is alternatively spliced [22], another way to
classify mutations is whether they affect both lamin A and
lamin C or just one protein. Of the 12 exons in LMNA, exons
11 and 12 are specific to lamin A, while alternative splicing at
codon 566 in exon 10 gives lamin C, a unique exon coding for
six amino acid residues (Figure 1). As expected given its size,
only two mutations, R571S causing DCM [23] and R571C
causing muscular dystrophy with axonal neuropathy [24],
have been associated with the lamin C-specific tail. Exon
12 encodes eight amino acids that are cleaved during posttranslational modification of prelamin A, so unless mutations
affect prelamin A processing, they would not be expected
to affect lamin A function. Interestingly, few mutations
occur in lamin A-specific exon 11 and those that do are less
C The
C 2010 Biochemical Society
Authors Journal compilation 259
260
Biochemical Society Transactions (2010) Volume 38, part 1
associated with skeletal muscle involvement: for example, of
18 mutations in exon 11 [1], 56% (10/18) cause DCM and
33% (6/18) result in FPLD2, with only one each causing
A-EDMD or LGMD1B (J. Scharner, V. Gnocchi, J.A. Ellis
and P.S. Zammit, unpublished work). It is worth noting that
as HGPS predominately, but not exclusively, targets lamin
A and generates the most severe laminopathy, it has been
interpreted as being the more important protein. However,
the apparent normal phenotype of the lmnaLCO/LCO mouse,
where lamin C is the only A-type lamin present, suggests that
both lamin A and the other isoforms are dispensable [25].
Effect of modifying genes and SNPs (single
nucleotide polymorphisms) on phenotypic
variability in laminopathies
Patients carrying, for example, the R644C mutation have
a range of clinical conditions including DCM, LGMD2B,
atypical HGPS, lipodystrophy etc. [26–29]. This extreme
phenotypic variability indicates that genetic background
contributes to the disease diagnosed [29]. Furthermore, a
single mutation can result in DCM either with or without
A-EDMD. This provides evidence of epistasis, i.e. effects of
the mutated LMNA gene are altered by one or more other
genes, the so-called modifying genes (Figure 2c). There are,
indeed, rare examples of where an additional mutation in
either desmin or emerin results in a more severe disease than
might be expected from the LMNA mutation alone [30].
Where patients carry two different pathogenic LMNA
mutations, it is not unexpected that they develop a more
severe phenotype [31]. However, LMNA also contains SNPs
with no apparent pathological phenotype: of 40 on the Leiden
Open Variation Database (www.dmd.nl/lmna_seqvar.html),
75% (30/40) are silent mutations, and the rest are missense
mutations affecting the head (one), central rod (three) or
tail (six) domains (J. Scharner, V. Gnocchi, J.A. Ellis and
P.S. Zammit, unpublished work). Depending on the context
however, these mutations can cause disease: T528M or
M540T alone appear non-pathogenic, but when inherited
together, they result in an apparently typical HGPS but
without prelamin A accumulation [32]. Certainly, a particular
LMNA pathogenic mutation/SNP combination can increase
the penetrance of a phenotype, which offers an explanation
for intra- and inter-familiar variations [33], but may also alter
the clinical condition diagnosed: while the S583L mutation
normally causes FPLD2, when present with T528M it
results in FPLD1 [34]. Modifying genes/SNPs are likely
to explain inconclusive attempts to associate mutation
with laminopathy (Figure 2c), where, for example, a single
mutation has been reported to express phenotypic variability,
such as with R60G, Y267C, R377H/L and R644C (Figure 1).
Mouse models of laminopathies
Modelling diseases in mice is a powerful technology to explore genotype–phenotype correlations, disease mechanisms
C The
C 2010 Biochemical Society
Authors Journal compilation and potential therapies. The majority of laminopathies arise
from missense and frameshift mutations, but two nonsense
mutations have been reported: patients heterozygous for
Y259X have LGMD1B [35], but those heterozygous for
Q6X develop DCM [36,37] and mice heterozygous for the
targeted lmna null allele also develop a DCM phenotype [38].
The only LMNA-null homozygous subject identified carried
Y259X and died at birth, and lmna−/− mice are characterized
by postnatal growth retardation, muscular dystrophy, rapidly
progressive DCM and death by 4–8 weeks of age [39,40].
In humans, both the L530P and H222P mutations
cause A-EDMD. The H222P mouse recapitulates features
of A-EDMD [41], while L530P causes a phenotype akin
to HGPS, possibly due to the unintentional inclusion of
an additional splicing defect in the C-terminus [42]. The
N195K mutation causes DCM in humans and a DCM-like
phenotype in mice [43]. Importantly, the L530P, H222P
and N195K mouse models only show a phenotype when
homozygous for the mutant alides, in contrast with the
heterozygous state in patients. DCM with A-EDMD
resulting from the M371K mutation also causes a heart
phenotype in transgenic mice when under a heart-specific
promoter [44]. Collectively, these mutant mice illustrate that
aspects of human laminopathies can be successfully modelled
in mice, with all the attendant advantages over experimenting
on rare patient samples, but again emphasizes that genetic
background exerts an influence on the penetrance of the
condition, whether in mice or humans.
Conclusions and perspectives
It must be remembered that laminopathies are rare diseases,
and in many cases there are very few patients with a particular
mutation(s). That said, what can be concluded about
genotype–phenotype correlations? In laminopathies such as
HGPS, there is a high degree of consistency in the underlying mutation between patients, meaning that the disease
mechanism is likely to be common to that particular disorder.
There is also a degree of genotype–phenotype correlation
in FPLD2 for example, where many mutations are in the
Ig-like fold and so could have a common disease mechanism,
although the rest give little clue as to why they cause this
condition. For others however, including DCM, A-EDMD
and LGMD1B, there is a much weaker correlation between
mutation and disease (Figure 2). A-EDMD and FPLD2 may
differ owing to the degree to which a particular mutation
affects lamin A/C structure, but this does not, for example,
explain how different amino acid substitutions lead to a
specific phenotype. It should also be remembered that lamins
A and C are distinct proteins and mutations in the common
region of LMNA would generate two distinct mutated
proteins that could function differently to cause disease and
so need to be treated as individual entities [45].
Where a more severe or unexpected phenotype is found
with a particular LMNA mutation, a number of factors may
be contributing. Whether a mutation also affects cell cycle and
differentiation, in addition to nuclear structure, chromosome
Nuclear Envelope Disease and Chromatin Organization 2009
organization or transcriptional regulation, could certainly
contribute to disease onset and severity, but maybe even the
laminopathy diagnosed. The emerging evidence of modifying
genes and SNPs affecting laminopathies means that, in future,
it would be helpful if clinical data were to include the LMNAspecific SNPs, to determine if disease severity/diagnosis can
be linked to certain mutation/SNP combinations. Screening
LMNA for SNPs is also being used in non-laminopathies with
overlapping phenotypes, to determine whether there is any
correlation with disease severity [46]. Ultimately, genomewide sequencing would be needed to check for mutations in
all regulatory regions of LMNA and fully explore the correlation with modifying genes. Finally, EDMD is divided into
A-EDMD, and X-linked EDMD caused by mutations in
EMD, but together these account for only ∼50% [47]
of clinically diagnosed EDMD. Assuming that LMNA
mutations/SNPs have not been overlooked, mutations in
other genes may also result in disorders with a similar
phenotype [48]. Indeed, it was recently shown that
mutations in LAP2α can cause a condition similar to DCM
[49], whereas mutations in SYNE1 or FHL1 produce an
EDMD-like phenotype [50,51].
Funding
J.S. is supported by a Ph.D. studentship funded by the Biomedical
and Health School, King’s College London, and V.F.G. is funded
by The Medical Research Council [grant number G0700307]. The
P.S.Z. laboratory is supported by The Muscular Dystrophy Campaign,
The Wellcome Trust and OPTISTEM (contract 223098), through the
European Union 7th Framework Programme.
References
1 Szeverenyi, I., Cassidy, A.J., Chung, C.W., Lee, B.T., Common, J.E., Ogg,
S.C., Chen, H., Sim, S.Y., Goh, W.L., Ng, K.W. et al. (2008) The Human
Intermediate Filament Database: comprehensive information on a gene
family involved in many human diseases. Hum. Mutat. 29, 351–360
2 Broers, J.L., Ramaekers, F.C., Bonne, G., Yaou, R.B. and Hutchison, C.J.
(2006) Nuclear lamins: laminopathies and their role in premature
ageing. Physiol. Rev. 86, 967–1008
3 Freimer, N. and Sabatti, C. (2003) The human phenome project. Nat.
Genet. 34, 15–21
4 Hegele, R. (2005) LMNA mutation position predicts organ system
involvement in laminopathies. Clin. Genet. 68, 31–34
5 Scriver, C.R. (2004) After the genome – the phenome? J. Inherit. Metab.
Dis. 27, 305–317
6 Eriksson, M., Brown, W.T., Gordon, L.B., Glynn, M.W., Singer, J., Scott, L.,
Erdos, M.R., Robbins, C.M., Moses, T.Y., Berglund, P. et al. (2003)
Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford
progeria syndrome. Nature 423, 293–298
7 Moulson, C.L., Fong, L.G., Gardner, J.M., Farber, E.A., Go, G., Passariello,
A., Grange, D.K., Young, S.G. and Miner, J.H. (2007) Increased progerin
expression associated with unusual LMNA mutations causes severe
progeroid syndromes. Hum. Mutat. 28, 882–889
8 Ben Yaou, R., Muchir, A., Arimura, T., Massart, C., Demay, L., Richard, P.
and Bonne, G. (2005) Genetics of laminopathies. Novartis Found. Symp.
264, 81–90
9 Quijano-Roy, S., Mbieleu, B., Bonnemann, C.G., Jeannet, P.Y., Colomer, J.,
Clarke, N.F., Cuisset, J.M., Roper, H., De Meirleir, L., D’Amico, A. et al.
(2008) De novo LMNA mutations cause a new form of congenital
muscular dystrophy. Ann. Neurol. 64, 177–186
10 Lloyd, D.J., Trembath, R.C. and Shackleton, S. (2002) A novel interaction
between lamin A and SREBP1: implications for partial lipodystrophy and
other laminopathies. Hum. Mol. Genet. 11, 769–777
11 Bonne, G., Mercuri, E., Muchir, A., Urtizberea, A., Becane, H.M., Recan, D.,
Merlini, L., Wehnert, M., Boor, R., Reuner, U. et al. (2000) Clinical and
molecular genetic spectrum of autosomal dominant Emery–Dreifuss
muscular dystrophy due to mutations of the lamin A/C gene. Ann.
Neurol. 48, 170–180
12 Benedetti, S., Menditto, I., Degano, M., Rodolico, C., Merlini, L., D’Amico,
A., Palmucci, L., Berardinelli, A., Pegoraro, E., Trevisan, C.P. et al. (2007)
Phenotypic clustering of lamin A/C mutations in neuromuscular patients.
Neurology 69, 1285–1292
13 Dhe-Paganon, S., Werner, E.D., Chi, Y.I. and Shoelson, S.E. (2002)
Structure of the globular tail of nuclear lamin. J. Biol. Chem. 277,
17381–17384
14 Krimm, I., Ostlund, C., Gilquin, B., Couprie, J., Hossenlopp, P., Mornon, J.P.,
Bonne, G., Courvalin, J.C., Worman, H.J. and Zinn-Justin, S. (2002) The
Ig-like structure of the C-terminal domain of lamin A/C, mutated in
muscular dystrophies, cardiomyopathy, and partial lipodystrophy.
Structure 10, 811–823
15 Magracheva, E., Kozlov, S., Stewart, C.L., Wlodawer, A. and Zdanov, A.
(2009) Structure of the lamin A/C R482W mutant responsible for
dominant familial partial lipodystrophy (FPLD). Acta Crystallogr. Sect. F
Struct. Biol. Cryst. Commun. 65, 665–670
16 Breinig, S., Kervinen, J., Stith, L., Wasson, A.S., Fairman, R., Wlodawer, A.,
Zdanov, A. and Jaffe, E.K. (2003) Control of tetrapyrrole biosynthesis by
alternate quaternary forms of porphobilinogen synthase. Nat. Struct.
Biol. 10, 757–763
17 Favreau, C., Higuet, D., Courvalin, J.C. and Buendia, B. (2004) Expression
of a mutant lamin A that causes Emery–Dreifuss muscular dystrophy
inhibits in vitro differentiation of C2C12 myoblasts. Mol. Cell. Biol. 24,
1481–1492
18 Emerson, L.J., Holt, M.R., Wheeler, M.A., Wehnert, M., Parsons, M. and
Ellis, J.A. (2009) Defects in cell spreading and ERK1/2 activation in
fibroblasts with lamin A/C mutations. Biochim. Biophys. Acta 1792,
810–821
19 Markiewicz, E., Ledran, M. and Hutchison, C.J. (2005) Remodelling of the
nuclear lamina and nucleoskeleton is required for skeletal muscle
differentiation in vitro. J. Cell Sci. 118, 409–420
20 Zammit, P.S. (2008) All muscle satellite cells are equal, but are some
more equal than others? J. Cell Sci. 121, 2975–2982
21 Gnocchi, V.F., Ellis, J.A. and Zammit, P.S. (2008) Does satellite cell
dysfunction contribute to disease progression in Emery–Dreifuss
muscular dystrophy? Biochem. Soc. Trans. 36, 1344–1349
22 Lin, F. and Worman, H.J. (1993) Structural organization of the human
gene encoding nuclear lamin A and nuclear lamin C. J. Biol. Chem. 268,
16321–16326
23 Fatkin, D., MacRae, C., Sasaki, T., Wolff, M.R., Porcu, M., Frenneaux, M.,
Atherton, J., Vidaillet, Jr, H.J., Spudich, S. et al. (1999) Missense mutations
in the rod domain of the lamin A/C gene as causes of dilated
cardiomyopathy and conduction-system disease. N. Engl. J. Med. 341,
1715–1724
24 Benedetti, S., Bertini, E., Iannaccone, S., Angelini, C., Trisciani, M.,
Toniolo, D., Sferrazza, B., Carrera, P., Comi, G., Ferrari, M. et al. (2005)
Dominant LMNA mutations can cause combined muscular dystrophy and
peripheral neuropathy. J. Neurol. Neurosurg. Psychiatry 76, 1019–1021
25 Fong, L.G., Ng, J.K., Lammerding, J., Vickers, T.A., Meta, M., Cote, N.,
Gavino, B., Qiao, X., Chang, S.Y., Young, S.R. et al. (2006) Prelamin A and
lamin A appear to be dispensable in the nuclear lamina. J. Clin. Invest.
116, 743–752
26 Brown, C.A., Lanning, R.W., McKinney, K.Q., Salvino, A.R., Cherniske, E.,
Crowe, C.A., Darras, B.T., Gominak, S., Greenberg, C.R., Grosmann, C.
et al. (2001) Novel and recurrent mutations in lamin A/C in patients with
Emery–Dreifuss muscular dystrophy. Am. J. Med. Genet. 102, 359–367
27 Csoka, A.B., Cao, H., Sammak, P.J., Constantinescu, D., Schatten, G.P. and
Hegele, R.A. (2004) Novel lamin A/C gene (LMNA) mutations in atypical
progeroid syndromes. J. Med. Genet. 41, 304–308
28 Mercuri, E., Brown, S.C., Nihoyannopoulos, P., Poulton, J., Kinali, M.,
Richard, P., Piercy, R.J., Messina, S., Sewry, C., Burke, M.M. et al. (2005)
Extreme variability of skeletal and cardiac muscle involvement in
patients with mutations in exon 11 of the lamin A/C gene. Muscle
Nerve 31, 602–609
29 Rankin, J., Auer-Grumbach, M., Bagg, W., Colclough, K., Nguyen, T.D.,
Fenton-May, J., Hattersley, A., Hudson, J., Jardine, P., Josifova, D. et al.
(2008) Extreme phenotypic diversity and nonpenetrance in families with
the LMNA gene mutation R644C. Am. J. Med. Genet. A 146, 1530–1542
C The
C 2010 Biochemical Society
Authors Journal compilation 261
262
Biochemical Society Transactions (2010) Volume 38, part 1
30 Muntoni, F., Bonne, G., Goldfarb, L.G., Mercuri, E., Piercy, R.J., Burke, M.,
Yaou, R.B., Richard, P., Recan, D., Shatunov, A. et al. (2006) Disease
severity in dominant Emery Dreifuss is increased by mutations in both
emerin and desmin proteins. Brain 129, 1260–1268
31 Hegele, R.A., Cao, H., Anderson, C.M. and Hramiak, I.M. (2000)
Heterogeneity of nuclear lamin A mutations in Dunnigan-type familial
partial lipodystrophy. J. Clin. Endocrinol. Metab. 85, 3431–3435
32 Verstraeten, V.L., Broers, J.L., van Steensel, M.A., Zinn-Justin, S.,
Ramaekers, F.C., Steijlen, P.M., Kamps, M., Kuijpers, H.J., Merckx, D.,
Smeets, H.J. et al. (2006) Compound heterozygosity for mutations in
LMNA causes a progeria syndrome without prelamin A accumulation.
Hum. Mol. Genet. 15, 2509–2522
33 Ellis, J.A. (2006) Emery–Dreifuss muscular dystrophy at the nuclear
envelope: 10 years on. Cell. Mol. Life Sci. 63, 2702–2709
34 Savage, D.B., Soos, M.A., Powlson, A., O’Rahilly, S., McFarlane, I., Halsall,
D.J., Barroso, I., Thomas, E.L., Bell, J.D., Scobie, I. et al. (2004) Familial
partial lipodystrophy associated with compound heterozygosity for novel
mutations in the LMNA gene. Diabetologia 47, 753–756
35 van Engelen, B.G., Muchir, A., Hutchison, C.J., van der Kooi, A.J., Bonne, G.
and Lammens, M. (2005) The lethal phenotype of a homozygous
nonsense mutation in the lamin A/C gene. Neurology 64, 374–376
36 Bonne, G., Di Barletta, M.R., Varnous, S., Becane, H.M., Hammouda, E.H.,
Merlini, L., Muntoni, F., Greenberg, C.R., Gary, F., Urtizberea, J.A. et al.
(1999) Mutations in the gene encoding lamin A/C cause autosomal
dominant Emery–Dreifuss muscular dystrophy. Nat. Genet. 21, 285–288
37 Becane, H.M., Bonne, G., Varnous, S., Muchir, A., Ortega, V., Hammouda,
E.H., Urtizberea, J.A., Lavergne, T., Fardeau, M., Eymard, B. et al. (2000)
High incidence of sudden death with conduction system and myocardial
disease due to lamins A and C gene mutation. Pacing Clin. Electrophysiol.
23, 1661–1666
38 Wolf, C.M., Wang, L., Alcalai, R., Pizard, A., Burgon, P.G., Ahmad, F.,
Sherwood, M., Branco, D.M., Wakimoto, H., Fishman, G.I. et al. (2008)
Lamin A/C haploinsufficiency causes dilated cardiomyopathy and
apoptosis-triggered cardiac conduction system disease. J. Mol. Cell.
Cardiol. 44, 293–303
39 Sullivan, T., Escalante-Alcalde, D., Bhatt, H., Anver, M., Bhat, N.,
Nagashima, K., Stewart, C.L. and Burke, B. (1999) Loss of A-type lamin
expression compromises nuclear envelope integrity leading to muscular
dystrophy. J. Cell Biol. 147, 913–920
40 Nikolova, V., Leimena, C., McMahon, A.C., Tan, J.C., Chandar, S., Jogia, D.,
Kesteven, S.H., Michalicek, J., Otway, R., Verheyen, F. et al. (2004)
Defects in nuclear structure and function promote dilated
cardiomyopathy in lamin A/C-deficient mice. J. Clin. Invest. 113,
357–369
41 Arimura, T., Helbling-Leclerc, A., Massart, C., Varnous, S., Niel, F., Lacene,
E., Fromes, Y., Toussaint, M., Mura, A.M., Keller, D.I. et al. (2005) Mouse
model carrying H222P-Lmna mutation develops muscular dystrophy and
dilated cardiomyopathy similar to human striated muscle laminopathies.
Hum. Mol. Genet. 14, 155–169
C The
C 2010 Biochemical Society
Authors Journal compilation 42 Mounkes, L.C., Kozlov, S., Hernandez, L., Sullivan, T. and Stewart, C.L.
(2003) A progeroid syndrome in mice is caused by defects in A-type
lamins. Nature 423, 298–301
43 Mounkes, L.C., Kozlov, S.V., Rottman, J.N. and Stewart, C.L. (2005)
Expression of an LMNA-N195K variant of A-type lamins results in cardiac
conduction defects and death in mice. Hum. Mol. Genet. 14, 2167–2180
44 Wang, Y., Herron, A.J. and Worman, H.J. (2006) Pathology and nuclear
abnormalities in hearts of transgenic mice expressing M371K lamin A
encoded by an LMNA mutation causing Emery–Dreifuss muscular
dystrophy. Hum. Mol. Genet. 15, 2479–2489
45 Motsch, I., Kaluarachchi, M., Emerson, L.J., Brown, C.A., Brown, S.C.,
Dabauvalle, M.C. and Ellis, J.A. (2005) Lamins A and C are differentially
dysfunctional in autosomal dominant Emery–Dreifuss muscular
dystrophy. Eur. J. Cell Biol. 84, 765–781
46 Gaudy-Marqueste, C., Boyer, A., Navarro, C., Rouzier, C., Harley, J.R.,
Weiller, P.J., Grob, J.J., Levy, N. and De Sandre-Giovannoli, A. (2009)
LMNA, ZMPSTE24, and LBR are not mutated in Scleroderma. Genet. Test.
Mol. Biomarkers 13, 635–639
47 Cohen, T.V. and Stewart, C.L. (2008) Fraying at the edge: mouse models
of diseases resulting from defects at the nuclear periphery. Curr. Top.
Dev. Biol. 84, 351–384
48 Stewart, C.L., Kozlov, S., Fong, L.G. and Young, S.G. (2007) Mouse models
of the laminopathies. Exp. Cell Res. 313, 2144–2156
49 Taylor, M.R., Slavov, D., Gajewski, A., Vlcek, S., Ku, L., Fain, P.R., Carniel,
E., Di Lenarda, A., Sinagra, G., Boucek, M.M. et al. (2005) Thymopoietin
(lamina-associated polypeptide 2) gene mutation associated with
dilated cardiomyopathy. Hum. Mutat. 26, 566–574
50 Zhang, Q., Bethmann, C., Worth, N.F., Davies, J.D., Wasner, C., Feuer, A.,
Ragnauth, C.D., Yi, Q., Mellad, J.A., Warren, D.T. et al. (2007) Nesprin-1
and -2 are involved in the pathogenesis of Emery–Dreifuss muscular
dystrophy and are critical for nuclear envelope integrity. Hum. Mol.
Genet. 16, 2816–2833
51 Gueneau, L., Bertrand, A.T., Jais, J.P., Salih, M.A., Stojkovic, T., Wehnert,
M., Hoeltzenbein, M., Spuler, S., Saitoh, S., Verschueren, A. et al. (2009)
Mutations of the FHL1 gene cause Emery–Dreifuss muscular dystrophy.
Am. J. Hum. Genet. 85, 338–353
52 Cao, H. and Hegele, R.A. (2003) LMNA is mutated in Hutchinson–Gilford
progeria (MIM 176670) but not in Wiedemann–Rautenstrauch progeroid
syndrome (MIM 264090). J. Hum. Genet. 48, 271–274
53 Agarwal, A.K., Kazachkova, I., Ten, S. and Garg, A. (2008) Severe
mandibuloacral dysplasia-associated lipodystrophy and progeria in a
young girl with a novel homozygous Arg527Cys LMNA mutation. J. Clin.
Endocrinol. Metab. 93, 4617–4623
54 Schirmer, E.C. and Foisner, R. (2007) Proteins that associate with lamins:
many faces, many functions. Exp. Cell Res. 313, 2167–2179
Received 28 August 2009
doi:10.1042/BST0380257