Advances in basic and clinical research in laminopathies.
ABSTRACT Lamins (LMNA) are the main proteins of the nuclear lamina considered to be the ancestors of all intermediate filament proteins. They form complex protein assemblies with integral proteins of the inner nuclear membrane, transcriptional regulators, histones and chromatin modifiers. During recent years, interest in lamins has greatly increased due to the identification of many distinct heritable human disorders associated with lamin mutations. These disorders, collectively termed laminopathies, range from muscular dystrophies to premature aging. They may affect muscle, fat, bone, nerve and skin tissues. The workshop was addressed to understand lamin organization and its roles in nuclear processes, mutations in lamins affecting cell and tissues functions, the biology of the nucleus and laminopathic disease mechanisms, all aspects important for designing future therapies.
- New England Journal of Medicine 02/2006; 354(2):209-10. · 51.66 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: The nuclear envelope has long been a focus of basic research for a highly specialized group of cell biologists. More recently, an expanding group of scientists and physicians have developed a keen interest in the nuclear envelope since mutations in the genes encoding lamins and associated proteins have been shown to cause a diverse range of human diseases often called laminopathies or nuclear envelopathies. Most of these diseases have tissue-selective phenotypes, suggesting that the nuclear envelope must function in cell-type- and developmental-stage-specific processes such as chromatin organization, regulation of gene expression, controlled nucleocytoplasmic transport and response to stress in metazoans. On 22-23 April 2009, Professor Christopher Hutchison organized the 4th British Nuclear Envelope Disease and Chromatin Organization meeting at the College of St Hild and St Bede at Durham University, sponsored by the Biochemical Society. In attendance were investigators with one common interest, the nuclear envelope, but with diverse expertise and training in animal and plant cell biology, genetics, developmental biology and medicine. We were each honoured to be keynote speakers. This issue of Biochemical Society Transactions contains papers written by some of the presenters at this scientifically exciting meeting, held in a bucolic setting where the food was tasty and the wine flowed freely. Perhaps at the end of this excellent meeting more questions were raised than answered, which will stimulate future research. However, what became clear is that the nuclear envelope is a cellular structure with critical functions in addition to its traditional role as a barrier separating the nuclear and cytoplasmic compartments in interphase eukaryotic cells.Biochemical Society Transactions 02/2010; 38(Pt 1):253-6. · 2.59 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Sixty-five members of three families with limb girdle muscular dystrophy (LGMD) underwent neurological, cardiological, and ancillary investigations. Thirty-five individuals were diagnosed as having slowly progressive autosomal dominant LGMD. Symmetrical weakness started in the proximal lower limb muscles, and gradually upper limb muscles also became affected. Early contractures of the spine were absent. Contractures of elbows and Achilles tendons were either minimal or late. Serum creatine kinase activity was normal to moderately elevated. Electromyogram and muscle biopsy were consistent with a mild muscular dystrophy. Cardiological abnormalities, found in more than one-half the patients, included dysrhythmias and atrioventricular (AV) conduction disturbances presenting as bradycardia, syncopal attacks necessitating pacemaker implantation, and sudden cardiac death. There was a significant relation between the severity of AV conduction disturbances and age. In nearly all patients, neuromuscular symptomatology preceded cardiological involvement. The early recognition of this previously not described, autosomal dominant LGMD with life-threatening cardiac involvement offers an opportunity for therapeutic intervention.Annals of Neurology 06/1996; 39(5):636-42. · 11.19 Impact Factor
Advances in basic and clinical research
Luisa Politano1, Nicola Carboni2, Agnieszka Madej-Pilarczyk3, Michael Marchel4,
Gerardo Nigro5, Anna FidziaŃska3, Grzegorz Opolski4 and Irena Hausmanowa-Petrusewicz3
1 Cardiomyology and Medical Genetics, Department of Experimental Medicine, Second University of Naples, Italy; 2 Dipartimento
di Sanità Pubblica, Medicina Clinica e Molecolare, Cagliari University, Italy; 3 Neurorepair Department, Mossakowski Medical
Research Centre, Warsaw, Poland; 4 Department of Cardiology, Medical University of Warsaw, Warsaw, Poland; 5 Arrhythmologic
Unit, Department of Cardiothoracic Sciences, Second University of Naples, Italy
Acta Myologica • 2013; XXXII: p. 18-22
Address for correspondence: Luisa Politano, Cardiomiologia e Genetica Medica, I Policlinico, piazza Miraglia, 80138 Napoli, Italy.
Lamins (LMNA) are the main proteins of the nuclear lamina
considered to be the ancestors of all intermediate filament pro-
teins. They form complex protein assemblies with integral pro-
teins of the inner nuclear membrane, transcriptional regulators,
histones and chromatin modifiers. During recent years, interest
in lamins has greatly increased due to the identification of many
distinct heritable human disorders associated with lamin muta-
tions. These disorders, collectively termed laminopathies, range
from muscular dystrophies to premature aging. They may affect
muscle, fat, bone, nerve and skin tissues. The workshop was ad-
dressed to understand lamin organization and its roles in nuclear
processes, mutations in lamins affecting cell and tissues functions,
the biology of the nucleus and laminopathic disease mechanisms,
all aspects important for designing future therapies.
Key words: LMNA A/C gene, laminopathies, Emery-Dreifuss
A workshop dedicated to the advances in basic and
clinical aspects of laminopathies was held in Warsaw,
last 29-30th November 2012, organized by Irena Haus-
manowa-Petrusewicz. The congress was scheduled as a
two days format, the former dedicated to the advances
in basic research, the latter to the advances in clinical re-
search in the field of laminopathies.
Lamins (LMNA) are the main proteins of the nuclear
lamina considered to be the ancestors of all intermedi-
ate filament proteins (1). They form complex protein
assemblies with integral proteins of the inner nuclear
membrane, transcriptional regulators, histones and chro-
matin modifiers. During recent years, interest in lamins
has greatly increased due to the identification of many
distinct heritable human disorders associated with lamin
mutations. These disorders, collectively termed lami-
nopathies, range from muscular dystrophies to premature
aging. They may affect muscle, fat, bone, nerve and skin
tissues. Understanding lamin organization, its roles in nu-
clear processes and why mutations in lamins affect cell
and tissues functions is important for understanding the
biology of the nucleus and laminopathic disease mecha-
nisms, as far as for designing future therapies.
Effect of nuclear lamina and
epigenetics in ageing mechanisms
Y. Gruenbaum showed the results obtained with his
coworkers D.Z. Bar and M. Davidovich on the regulation
of aging, by the C. elegans nuclear lamina. Lamins and
most of their functions are conserved in Caenorhabditis
elegans (2). Although linked to premature aging diseases,
they have yet to be linked to any of the major lifespan reg-
ulating pathways, thus leaving a gap in the understanding
of the lamins’ role in natural aging. Dietary restriction
(DR) acts via conserved pathways to enable better cell
maintenance and prolongs lifespan and health-span in
multiple organisms. In Caenorhabditis elegans, multiple
aspects of DR are regulated by lamin, including animal
length and fat content, in a pathway mediated by S6K and
SREBP. Furthermore, some aspects of DR are regulated
Advances in basic and clinical research in laminopathies
neurons and glia cells. She concluded that cultured lines
of these stem cells could provide a valuable authologous
material for transplantation to patients that present with
Role of lamins in chromatin
R. Foisner presented his studies aimed at clarifying
the role of nucleoplasmic lamins in chromatin organiza-
tion and possible implications for laminopathies (17).
He has identified a nucleoplasmic A-type lamin-binding
protein, termed Lamin-associated Polypeptide 2 alpha
(LAP2α) (18), which impairs assembly of A-type lamins
at the nuclear lamina and maintains a pool of soluble,
mobile A-type lamins throughout the nucleus. He also
showed that a nucleoplasmic complex of A-type lamins
and LAP2α increases the repressor activity of the cell
cycle regulatory retinoblastoma protein (pRb). Further-
more the deletion of the Lap2α gene in mice causes loss
of nucleoplasmic lamins and a deregulation of pRb-me-
diated gene expression, leading to hyperproliferation of
tissue progenitor cells and hyperplasia of the tissue (18).
He proposed a model in which a nucleoplasmic pool of
lamins is involved in the regulation of chromatin struc-
ture and function in tissue progenitor cells during tissue
regeneration; he postulated that mutations in lamins can
alter the ratio of nucleoplasmic versus peripheral lamins
and thereby affect tissue progenitor cells and tissue re-
Role of mutated lamin A
and emerin proteins in development
of abnormal phenotypes
and prospects for gene therapy
This particular aspect of lamins was illustrated by R.
Rzepecki. Mutations in LMNA and STA genes affect ma-
jor cellular pathways regulating the development, main-
tenance and regeneration of tissues, mostly cardiac and
skeletal muscles, of mesodermal origin. Lamin A, lamin
B, emerin, NET25, NET39 and MAN1 (LEMD3) pro-
teins modulate such signaling pathways e.g.: Wnt, TGFβ/
BMP/activin, MAPKs, mTOR, Akt, PKC (19). Most of
these pathways interconnect themselves and with many
other pathways giving rise to the differences in manifes-
tations of disease phenotypes. Preliminary reports dem-
onstrate the possibility to use gene/cell therapy for the
muscular dystrophy type of laminopathies as well as for
HGPS Progeria. Strategies for gene therapy for AR type
of laminopathies seem to be the simplest, while the pros-
pect gene therapy treatment of AD laminopathies seems
by specific changes in proteins at the nuclear envelope. C.
Hutchison presented his studies on the role of lamin A in
senescence in normal and premature ageing (3-5).
M. Puzianowska-Kuznicka reported the results ob-
tained by her work group (M. Budzinska, M. Owczarz,
E. Pawlik-Pachucka and J. Połosak) on epigenetics of
immunosenescence. Aging results from accumulation
of a stochastic damage to DNA, proteins, and to lipids.
Its rate and clinical course depend on genetic, environ-
mental, and stochastic factors. Studies performed on mo-
nozygotic twins (6) suggest that up to the age of 85, the
rate of aging depends on genes only up to 35%, but the
role of genetic factors increases thereafter. Genes poten-
tially contributing to aging of humans are these encoding
proteins involved in the insulin and insulin-like growth
factor-1 (7) pathways, genes encoding sirtuins (8), lamin
A/C, apolipoprotein E, enzymes de-activating the reactive
oxygen species, and genes encoding proteins involved in
DNA repair. Aging is accompanied by epigenetic drift, an
age-related, tissue-specific change in the pattern of epige-
netic modifications, that in a large part is a result of life-
long exposure to various environmental factors (9, 10).
Age-related alterations of function of blood mononuclear
cells might be, in part, a result of epigenetic drift affecting
the level of expression of various genes. She showed that
the expression of IGF-1R, FOXO1, FOXO3a, SIRT1-7,
WRN, XPD, THRA and THRB genes significantly de-
creased with age (11, 12), in a different way.
Pathogenesis of laminopathies
The role of mesenchymal stem cells in the patho-
genesis of Hutchincon-Gilford progeria syndrome was
discussed by K. Domańska-Janik. Hutchinson-Gilford
progeria syndrome (HGPS) is a sporadic genetic disease,
extremely rare, linked with mutations of LMNA gene,
presenting specific features of premature aging. A pro-
gressive deterioration of the various mesenchymal de-
rived tissues was observed in laminopathies (13), leading
in the past to hypothesize that the dysfunction of mesen-
chymal stem cells (MSCs) might be a specific target for
mutation (14). Recent studies on the processes of matura-
tion in the context of somatic stem cell biology have sug-
gested that other hypotheses addressing the role of MSCs
in the pathology of progeria would be equally plausible.
Among them, the hypothesis of Melton and Cowan (15),
which suggests that somatic stem cells residing in their
tissue-specific niches are not necessarily part of a clas-
sical developmental continuum, but they may arise as a
distinct pluripotent, embryonic-like stem cell lineage
separated from the main stream of organogenesis (16).
These cells could be grown in vitro for a long time as
non-immortalized cell lines and differentiate also toward
Luisa Politano et al.
hearts of LMNA mutated (H222P/H222P) mice recently
The usefulness of not invasive elettrocardiographic
parameters such as QTc dispersion (QTc-D), JTc disper-
sion (JTc-D) and Tpeak-end dispersion (TDR), that reflect
the physiological variability of regional and transmural
ventricular repolarisation and provide a substrate for life-
threatening ventricular arrhythmias was also stressed. In
the experience of the Naples group, EDMD is associated
with increased heterogeneity of ventricular repolarisation
even in the absence of impaired systolic and diastolic car-
diac function (32-33).
The last two lectures were dedicated to the descrip-
tion of LMNA prevalence in two different realities: the
Sardinia isle in Italy and the Poland country.
N. Carboni showed his database including 46 sub-
jects with LMNA gene mutations, all but 1 familial cases.
He presented one of the families showing familial dilated
cardiomyopathy with conduction defects due to mutation
in Lamin A/C gene (28). Patients with overlapping syn-
dromes, obtained by the concomitant presence of cardiac
compromise, late lipodystrophy of the Dunnigan type,
diabetes and axonal neuropathy (34) and a series of pic-
tures of lower limbs muscle MRI were shown. Despite
the different (prevalently cardiac or muscle) phenotype,
all patients had a similar pattern of posterior leg’s mus-
cles involvement, affecting medial head of gastrocne-
mius, sartorius and lateral head of gastrocnemius (35).
Follow up studies on larger cohorts of patients are to be
encouraged and the experience of the Italian Centre for
Laminopathies taken as an example of a fruitful collabo-
ration (36, 37).
Irena Hausmanowa-Petrusewicz concluded the con-
gress reporting various aspects of laminopathies in Po-
land. She said: “Our adventure with laminopathies started
long time ago when we, by chance, got for consultation
the patient whom we were unable to recognize as were
also same with local doctors. The diagnosis in this pa-
tient was made by British colleagues, who recognized
laminopathy, which was a terminology unknown to us.
In spite of this we began fascinated by this problem. We
started and still are working on laminopathies (38, 39).
The historic patient was a member of huge family P., af-
fected by emerinopathy (mutation in EMD gene). We
had access many members of this family. The patients
were only males, and we checked carriers, who were
mostly fifty or sixty year old females, developing at this
age cardiac symptoms. Such cardiac symptoms became
clear to us as a part of clinical picture, following mus-
cle involvement and joint contractures. Quite soon after
identification of the second gene associated with similar
clinical presentation we found also in Poland many cases
which had the same phenotype, resulting from muta-
to be much more complicated (20). Lentivirus vector sys-
tem for delivery of genetic drug represents a model of
universal gene therapy strategy for muscle laminopathies
and HGPS progeria.
Clinical aspects of laminopathies
The second day was opened by G. Opolski who
stressed the variety of LMNA clinical phenotypes, most
of them with cardiac involvement, frequently character-
ized by arrhythmias and dilated cardiomyopathy (DCM).
He presented a brief history of research in laminopathies
within the field of cardiology, starting from the first de-
scription of a DCM case due to LMNA mutation (21),
to case series of DCM with atrio-ventricular conduction
defects, the natural history of LMNA DCM underlying
the poor prognosis and the high risk of sudden cardiac
death (SCD) in these patients. His series comprised 34
pts with genetically confirmed EDMD [24 pts with an X-
linked inheritance (defect in the STA gene, emerinopa-
thy) and 10 pts with an autosomal dominant form (de-
fect in LMNA, laminopathy)], compared with 25 healthy
volunteers. G. Opolski showed that cardiac involvement
was independent of the severity of skeletal muscle dis-
ease, and that both left ventricular systolic (24%) and
diastolic dysfunction (41%) are very common and re-
sponsible for a high risk of sudden death. Early detection
of cardiac conduction disorders may be life-saving in pts
with cardiomyopathy and LMNA mutation. He presented
the guide-lines for the management of these patients, that
follows the standards of treatment for heart failure and
recommended ICD implantation also in patients requiring
pacing who do not meet generally accepted criteria for
ICD in the general population (22-24).
L. Politano presented a combined talk dealing with
the wide spectrum of myo-cardiolaminopathies in hu-
mans, and the treatment of arrhythmic events in lami-
nopathies, in collaboration with Gerardo Nigro. Different
clinical presentations associated with mutations in LM-
NA gene, ranging from classical AD-EDMD phenotype
involving both skeletal muscles and myocardium (25,
26), to LGMD phenotype (27), “pure” cardiac presenta-
tion as brady-arrhythmias (sino-atrial or atrio-ventricular
blocks of several degree) or tachy-arrhythmias (atrial or
ventricular fibrillation or flutter, ventricular tachycar-
dia) without any skeletal muscle involvement (28) were
shown. Particular emphasis was done on the congenital
phenotype of laminopathies, presenting as a congenital
muscular dystrophy (29) but associated with a high fre-
quency of arrhythmias and risk of SCD. Future therapeu-
tic possibilities arising from drugs enhancing autophagy
such as temsirolimus, or from MTOR blockade (30),
were presented on the basis of a defective autophagy in
Advances in basic and clinical research in laminopathies
brew University of Jerusalem, Israel
Irena Hausmanowa-Petrusewicz, Neuromuscular
Unit, Mossakowski Medical Research Center, Polish
Academy of Science, Warsaw, Poland
Chris Hutchison, School of Biological and Biomedi-
cal Sciences, Durham University, UK
Agnieszka Madej-Pilarczyk, Neuromuscular Unit,
Mossakowski Medical Research Center, Polish Academy
of Science, Warsaw, Poland
Michal Marchel, 1st Department of Cardiology,
Medical University of Warsaw, Warsaw, Poland
Grzegorz Opolski, 1st Department of Cardiology,
Medical University of Warsaw, Warsaw, Poland
Luisa Politano, Cardiomyology and Medical Genet-
ics, Second University of Naples, Naples, Italy
Monika Puzianowska-Kuznicka, Department of Hu-
man Epigenetics, Mossakowski Medical Research Cen-
tre, Warsaw, Poland; Department of Geriatrics and Ger-
ontology, Medical Centre of Postgraduate Education,
Ryszard Rzepecki, Laboratory of Nuclear Proteins
and 2Laboratory of Cytobiochemistry, Department of
Biotechnology, University of Wrocław, Poland
Dr. Foisner work is funded by grants of the Austrian
Science Fund (FWF).
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most fascinating problem became to us the striking vari-
ability (inter- and intrafamiliar) of phenotype in lamino-
pathic disorders. Our clinical activity was concentrated
on therapy, provided by the Department of cardiology,
chaired by prof. Opolski (39). In the following years we
started to look for patients in the clinical centers of our
country and as a result we became still modest, but any-
way leading center of laminopathies in Poland. We rec-
ognized better the pathology of nuclear proteins i.a. that
expressed in other tissues, manifesting as lipodystrophy,
peripheral neuropathy, isolated cardiomyopathy and pro-
geria. In the meantime our colleagues became interested
in some specific problems in laminopathies: Niebrój-
Dobosz – in biomarkers (40-42), which turned out to be
important for diagnosis and prognosis in cardiac involve-
ment; Fidziańska – in ultrastructural analysis of affected
myocytes indicating characteristic structural changes of
nuclei (43). The last issue till now, which arose our inter-
est were laminopathies in children, i.e. congenital dystro-
phy, restrictive dermopathy and progeria, which lead us to
problem of premature aging. Madej-Pilarczyk described
a large family affected by overlapping syndrome of prog-
eria and restrictive dermopathy, associated with homozy-
gous mutation in LMNA gene (44). Our next step would
be continuation of present work with special attention on
the role of laminopathies in development and in normal
and premature aging”.
Fruitful discussion during all the meeting clarified
different points of view, and constructively resulted in a
proposal for a wide European collaboration. The inter-
disciplinary approach to laminopathies was highly en-
couraged. This was an enjoyable and fruitful workshop
that will lead to new collaborations and will contribute
significantly to the improvement of future therapeutic
perspectives in laminopathies.
List of participants
Nicola Carboni, Department of Public Health, Mo-
lecular and Cellular Medicine, University of Cagliari, Italy
Krystyna Domańska-Janik, Neurorepair Department,
Mossakowski Medical Research Centre, Warsaw, Poland
Anna Fidziańska, Neuromuscular Unit, Mossakows-
ki Medical Research Center, Polish Academy of Science,
Roland Foisner, Max F Perutz Laboratories, Medical
University Vienna, Vienna, Austria
Yosef Gruenbaum, Department of Genetics, The
Alexander Silberman Institute of Life Sciences, The He-
Luisa Politano et al.
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