| | 141st ENMC International Workshop Inaugural Meeting of the EURO-Laminopathies Project Nuclear Envelope-linked Rare Human Diseases: From Molecular Pathophysiology towards Clinical Applications 10–12 March 2006, Naarden, The NetherlandsReceived 16 March 2007 1. Introduction  EURO-Laminopathies is a European Commission-funded research project, including 13 scientific group leaders in the fields of human genetics, clinical research, structural biology, molecular cell biology, and pharmaceutical industry, and one administrative manager from eight countries (Austria, France, Germany, Italy Israel, Spain, Switzerland and the United Kingdom). The consortium held its kick-off meeting as an International ENMC Workshop in Naarden on the weekend of March 10–12, 2006. The EURO-Laminopathies project aims at understanding the molecular mechanisms of laminopathies, which are rare human diseases linked to mutations in genes encoding nuclear envelope proteins, such as A-type lamins (LMNA), proteins involved in the post-translational processing of A-type lamins (ZMPSTE24), and lamin-binding proteins (EMD, LBR, LAP2). Laminopathies are clinically manifested after birth, can affect different tissues and progressively develop during childhood or adolescence, often leading to early death. Efficient therapies have been hampered by the lack of understanding the molecular disease mechanisms. The ultimate goal of the project thus is to identify reliable diagnostic markers and drug targets in order to rationally develop new therapeutic interventions and to improve existing therapies for laminopathy patients. During the workshop, new insights into the clinical and genetic spectrum of laminopathies and into clinical trials on the treatment of lipodystrophy-type laminopathy patients were given and future prospects on novel therapeutic approaches and theranostic tests for the validation of therapies were presented. Furthermore, the consortium discussed clinical and basic research approaches in order to analyze the effects of disease-causing mutations in A-type lamins and in one of their prominent binding partners, Lamina-associated polypeptide 2-alpha (LAP2α) on the atomic structure, interactions, and assembly properties of the proteins and on their potential roles in chromatin organization, gene expression, and differentiation of adult muscle and adipose stem cells. 2. Background Lamins are major architectural proteins in the nuclei of eukaryotic cells [1], [2]. B-type lamins are expressed in all cells and are essential for cell viability, while A-type lamins are expressed primarily in differentiated cells and are involved in tissue homeostasis and function. Mutations in A-type lamins and their binding partners cause a variety of disease phenotypes, collectively called laminopathies [3], [4]. These diseases can affect muscle, adipose, nerve, bone, and skin tissues or cause premature ageing. Based on known and proposed functions of lamins, various disease hypotheses have been proposed to explain the molecular basis of laminopathies, but it remains unclear how much a particular disease mechanism can contribute to a given clinical phenotype [2], [5], [6]. The mechanical hypothesis predicts that mutations in lamins and lamin-binding proteins alter their structure and weaken their stability, either by interfering with proper folding of the proteins or by affecting the assembly of lamina protein complexes, thereby predisposing cells and tissues to physical damage. This model seems reasonable particularly for muscle tissue, as lamins provide structural stability to the nucleus and muscle is exposed to physical stress. In line with this hypothesis, laminopathy patient often have structural abnormalities of their cell nuclei. However, the structural disease model cannot explain all clinical pathologies, as unaffected tissues also show deformed nuclei. The gene expression hypothesis proposes that mutations in lamins disrupt interactions of lamins with transcriptional regulators, such as the adipocyte-specific transcription factor sterol response element binding protein, and affect tissue-specific patterns of gene expression. Furthermore, lamins are also involved in epigenetic pathways regulating heterochromatin formation through numerous interactions of lamin complexes with DNA and chromatin proteins [7]. Mutations in A-type lamins may cause gross changes in higher order chromatin structure and gene expression. In line with this hypothesis nuclei from patient cells often lack the peripheral heterochromatin. The cell proliferation/differentiation hypothesis is mainly based on the in vivo interaction between lamins A/C and LAP2α and the tumor suppressor retinoblastoma protein [8], [9], which is required for muscle and adipocyte differentiation. It has been suggested that stem cells in laminopathy patients have a defective differentiation potential and cannot effectively regenerate tissues. 3. Genetic and clinical features of laminopathies Disease-causing mutations are currently reported for 11 genes encoding nuclear envelope components (LMNA, LMNB1, LMNB2, EMD, LAP2, LBR, LEMD3, ZMPSTE24, SYNE-1, NUP62, DYT1). Among them, the major group of diseases is caused either by mutations in the lamin A/C gene (i.e. primary laminopathies) or by mutations in the ZMPSTE24 gene affecting the correct post-translational processing of prelamin A and thus considered as secondary laminopathies. Primary laminopathies can be classified into 5 types affecting either specific tissue in isolated fashion, i.e. (1) the striated muscles, (2) the peripheral nerves, and (3) the adipose tissue; or in a systemic way several tissues with (4) the premature ageing syndromes and their related disorders, named also “systemic laminopathies”. Finally, numerous heterogeneous clinical situations have been reported and form the fifth group of disorders that comprise overlapping phenotypes characterized by the coexistence of two or more tissue involvements, suggesting a real continuum within the different types of laminopathies [3]. Gisèle Bonne, Jacqueline Capeau, Nicolas Lévy, and Manfred Wehnert reported that up to now, more than 211 mutations of the LMNA gene in more than 1037 individuals have been identified, of whom about 60% presented laminopathies affecting the striated muscles (Emery Dreifuss Muscular Dystrophy; Limb Girdle Muscular Dystrophy; Dilated Cardiomyopathy with Conduction Defects), 25% laminopathies affecting the adipose issue (Dunningan type familial partial lipodystrophy), 6% presented with premature aging syndromes (Hutchinson–Gilford Progeria; Atypical Werner Syndrome) and 3% with axonal neuropathies. Faced with this very wide diversity, a Universal mutation database (UMD)-LMNA database has been established which brings together all the clinical and genetic data concerning the mutations described by our networks as well as those reported in the literature (http://www.umd.be:2000). Similar UMD mutation databases were also created for the EMD (http://www.umd.be:2010) and ZMPSTE24 gene (soon available on the UMD web site). These mutation databases are useful tools for analyzing phenotype/genotype relation in this complex group of disorders. It was also discussed that in addition to mutations in the lamin A genes, an increasing number of lamin A-interacting proteins, such as emerin, LAP2α, and MAN1 have been linked to similar diseases showing clinically overlapping phenotypes with the lamin-linked laminopathies [3], [7]. The number of laminopathy-linked genes is likely to increase, since a growing number of patients with laminopathy-type pathologies do not have mutations in any of the known disease genes. In this context, the human geneticist and clinician partners of the EURO-Laminopathies consortium will mainly focus on: (1) the further description of LMNA, ZMPSTE24, EMD and LAP2 gene mutations and of the clinical spectrum of associated diseases, (2) the search for new genes responsible for closely related disorders in both a gene and a syndrome candidate approach, (3) the understanding of the clinical variability of these disorders through the analyses of possible phenotype/genotype relations as well as the identification of modifier genes and/or polymorphisms. 4. Molecular disease mechanisms 4.1. Lamin structure and assembly Lamins represent the principal molecular building blocks of the nuclear lamina, a filamentous meshwork closely adhering to the inner nuclear membrane. Based on their primary sequence lamins are members of the superfamily of intermediate filament proteins with a conserved tripartite domain organization, consisting of a central α-helical rod domain flanked by a short N-terminal head domain and a large globular C-terminal tail domain [10]. Harald Herrmann discussed studies on the in vitro assembly of lamins into filamentous and fibrous structures reminiscent of intermediate filament-like filaments and paracrystalline fibers [11]. However, whereas vertebrate cytoplasmic intermediate filament dimers first associate laterally into so-called unit-length filaments before these longitudinally anneal and radially compact to yield mature 10-nm filaments [12], lamin dimers first polymerize head-to-tail into long protofilaments before these associate laterally into filamentous and paracrystalline arrays [13]. The molecular basis for the different assembly pathways of cytoplasmic intermediate filaments and lamins is poorly understood but recent studies on the elucidation of the atomic structure of N- and C-terminal domains of the central rod domain, which are involved in the head to tail association of lamin dimers during assembly, brought first insights into potential interaction mechanisms. Ueli Aebi reported that the crystal structure of the coil 2B dimer of human lamin A revealed an overall structure similar to the homologous cytoplasmic intermediate filament segment in human vimentin [14], [15]. However, the distribution of charged residues and the patterns of intra- and interhelical salt bridges were different. Because of the described structural roles of lamins, it is widely believed that the lamina acts as a cellular equivalent of a tensegrity device, i.e. a load bearing structure that provides resilience and an ability to resist deformation forces [16]. Shear stress, for example, has been shown to induce structural remodeling of the nucleus [17]. Such physical stimuli may critically involve the nuclear lamina, not only as a nuclear architectural moiety but also as a ‘mechanical signal transducer’ coupling the cytoskeleton to the nuclear interior. Thus, an altered behavior or loss of resistance to mechanical stress may be a common phenomenon in laminopathies [18]. Furthermore, the lamina plays important roles in organizing peripheral chromatin, positioning the nuclear pore complexes within the nuclear envelope, and coupling the cytoskeleton to the nuclear envelope and the nuclear skeleton. The more than 200 different mutations in the LMNA gene, which give rise to the multiple disease phenotypes, have been reported to be spread across the entire gene sequence. As yet, the hypothesis that a particular lamin A mutation position determines the laminopathy phenotype has not been proven. So far, only one report documented that mutations within lamin A’s C-terminal Ig-like domain (residues 430–545), which destabilize its three-dimensional fold are causing muscular dystrophy. In contrast, charged residues residing on the surface of this domain that may be involved in the interaction of lamin A with other proteins are causing lipodystrophy when mutated [19]. Besides the Ig-fold and the above mentioned coil 2B, high resolution structures of other lamin domains are not available except for atomic models of coil 1A [15]. In order to reveal potential molecular consequences at the atomic level of disease-causing mutations in the LMNA and the LAP2α genes, the EURO-Laminopathies structural biology team proposed to elucidate the crystal structure of wild-type and disease variants of lamins and LAP2α. They will apply a ‘divide-and-conquer’ crystallographic approach based on the analysis of specifically designed protein fragments and complexes of fragments. Furthermore they presented plans to develop novel assays to test lamin in vitro assembly regimes and to investigate the molecular effects of disease-causing mutations on the assembly and mechanical stability of lamin complexes. 4.2. Nuclear and chromatin organization in laminopathies Cytological studies show that the position of chromatin in nuclei is not random. Each chromosome maintains a discrete domain within the nucleus [20], [21] and large proportions of condensed chromatin are localized at the nuclear periphery [22]. Furthermore, in mammalian cells, the position of chromosomes that are more transcriptionally active (chromosome 19, active X-chromosome) is more towards the interior of nuclei, whereas the gene-poor chromosomes (chromosome 18, inactive X-chromosome) are positioned towards the nuclear periphery [22], [23]. Joanna Bridger presented evidence that chromosome position may also be altered in cells containing specific LMNA mutations. It is now well established that lamins A/C are involved in chromatin organization at the nuclear periphery [2]. Nuclei of progeria fibroblasts expressing the mutant lamin A (LAΔ0) lose their peripheral heterochromatin and a histone methylation mark of pericentric heterochromatin (lysine 9 of histone H3) is reduced, as well as the association of this mark with heterochromatin protein 1α [23]. Interestingly, downregulation of the mutant lamin A (LAΔ0) restores the heterochromatin pattern at the nuclear periphery [24], demonstrating that expression of the mutated protein is directly linked to chromatin reorganization. Nadir Maraldi and Giovanna Lattanzi presented evidence that LNMA mutations in other laminopathies may also alter chromatin organization. For example, nuclei derived from familial partial lipodystrophy patient cells contain farnesylated lamin A (typically found in progeria [25]) and show chromatin abnormalities [26]. This also suggests a direct correlation between accumulation of farnesylated lamin A and chromatin defects in laminopathic disorders. Both pre-B-type lamins and prelamin A have a C-terminal CaaX motif that is subjected to several post-translational modifications [27]. First, the cysteine is farnesylated, then the last three residues are cleaved off and the cysteine undergoes methyl esterification. Prelamin A undergoes an additional cleavage that removes the 15 C-terminal amino acids, including the farnesyl group. Both cleavage steps in the maturation of lamin A are probably catalyzed by the zinc-metalloproteinase ZMPSTE24 and are dependent on the sequence of processing steps. In the majority of cases progeria-linked mutated lamin A cannot undergo the final proteolytic cleavage step due to a loss of the proteolytic cleavage site, thus staying permanently farnesylated. Giovanni Lattanzi and Nadir Maraldi are testing the effect of inhibiting each of these steps in lamin A maturation on chromatin organization, as a means of potential therapeutic interventions in patients. They showed that treatment of progeria cells with farnesyl-transferase inhibitors can rescue heterochromatin organization [28]. Do changes in cell shape, nuclear lamina composition and chromatin organization as seen in progeria fibroblasts also occur in normal cells that are getting old? Yosef Gruenbaum tested this hypothesis in Caenorhabditis elegans. They found that nuclear architecture in most non-neuronal cell types undergoes progressive and stochastic alteration as the animal ages and that the rate of this alteration is affected by mutations in the insulin/insulin-like growth factor like signaling pathway [29]. These changes are accompanied by changes in the distribution of heterochromatin markers. He also showed that reducing the levels of lamin and lamin-associated LEM domain proteins can lead to shortening of the life span. These data correlate with recent results showing that the LAΔ0 splicing isoform that is detected in progeria cells is also present in low amounts in normal cells [30]. 4.3. Lamins in the control of cell proliferation and differentiation Several transcriptional regulator proteins and signaling components can form lamin-dependent complexes, which regulate gene expression and signal transduction [2], [7]. A novel concept was presented by Roland Foisner and Chris Hutchison, postulating that in addition to the peripheral lamin complexes, lamins in the nucleoplasm also interact and control transcriptional regulators. Dorner et al. have recently reported that nucleoplasmic complexes of lamin A and LAP2α bind to the cell cycle regulator protein retinoblastoma (pRb) and affect its function in the E2F-pRb pathway that controls cell cycle progression and differentiation [8]. These findings are in line with other reports on lamin A-deficient mouse fibroblasts, providing evidence for the involvement of lamins in cell cycle arrest, by either stabilizing pRb protein [31] or by controlling its phosphorylation/dephosphorylation [32]. This has lead to the formulation of a novel intriguing disease model, proposing that mutations in lamin A or in lamin-binding proteins (emerin and LAP2α) can interfere with their functions in cell cycle control [5]. This would lead to an imbalance of cell proliferation versus differentiation in adult stem cells consequently impairing tissue homeostasis and regeneration. Indeed, expression of disease-causing lamin variants in myoblast cell cultures [33] or loss of lamin A expression [34] have been shown to impair muscle differentiation in vitro. Also, expression profiling of muscle tissue derived from Emery Dreifuss Muscular Dystrophy patients indicated a deregulation of the pRb/MyoD pathway which controls muscle differentiation [35]. Several members in the EURO-Laminopathies consortium will test this hypothesis by investigating in vitro and in vivo muscle and adipocyte differentiation in patient cells and in cells derived from available and newly established laminopathy mouse models (e.g. the knock-in mouse models expressing Emery Dreifuss Muscular Dystrophy-linked H222P lamin A variant [36]). In human fibroblasts Pekovic et al. recently found that loss of LAP2α and/or loss of nucleoplasmic lamin complexes in human fibroblasts caused an initial acceleration in cell cycle progression, but subsequently initiated cell cycle arrest and cellular senescence [9]. It will be extremely interesting to test whether this cellular phenotype is linked to pathologies detected in laminopathic patients. 5. Drug target search and therapeutic approaches Although laminopathies have become a subject of intense research in the past few years, the treatment of laminopathy is still an unresolved and extremely difficult issue mostly due to the plethora of different associated phenotypes. While no therapeutic approaches have been described yet for muscle-affecting diseases (except for implantation of pace makers or fibrilators), first trials of therapies have been undertaken in lipodystrophy patients. Lipodystrophies are generally characterized by selective loss of body fat [37]. The loss of adipose tissue is associated with increased prevalence of insulin resistance and its complications, such as impaired glucose tolerance, diabetes, hyperinsulinemia, dyslipidemia, hepatic steatosis, acanthosis nigricans, polycystic ovarian disease, and hypertension. As discussed at the workshop by Giuseppe Novelli and Jacqueline Capeau, the management of lipodystrophies is challenging, as patients often develop long-term complications of diabetes and accelerated atherosclerosis. Current and experimental therapeutic options include the use of peroxisome proliferator activated receptor gamma agonists, which stimulate differentiation of pre-adipocytes and increase body fat. Clinical experience in a subset of patients has been presented with promising results. Several other potential therapies have been considered on the basis of current understanding of the pathophysiology of insulin resistance and metabolic complications in patients with mandibuloacral dysplasia. In particular, Giuseppe Novelli, has provided evidence implicating the tumor necrosis factor-α in mandibuloacral dysplasia, and indicated the rationale for clinical studies of anti-tumor necrosis factor therapy in preventing osteolysis in mandibuloacral dysplasia. Based on the recent evidence of the link between abnormal lamin A processing (see above) and the observed molecular defects of some laminopathies, like Hutchinson–Gilford progeria, the feasibility of protein farnesyl-transferase inhibitors as drugs for treating those laminopathies characterized by accumulation of prelamin A has been discussed. Giovanna Lattanzi, presented preliminary evidence for the rescue of normal nuclear architecture in fibroblasts from patients with progeria and mandibuloacral dysplasia upon treatment with farnesyl transferase inhibitor in vitro. However, further work is needed to clearly demonstrate how the proposed clinical protocols influence the primary defect observed in laminopathies. Therefore, the identification and detailed analysis of biological mechanisms changed by mutated lamins is a reasonable approach for providing novel therapeutic targets for treating these diseases. Studies along these lines have been prospected by all participating groups, making us confident that the EURO-Laminopathies network will not only reveal details of lamin functions and their impairment by specific disease-causing mutations, but will also pave the road for the identification of novel drug targets and the rational development of more efficient, individualized therapies in the coming years. 6. List of participants Ueli Aebi, Biozentrum (Basel, Switzerland) Catherine Berens (EU, Brussels, Belgium) Gisèle Bonne (Paris, France) Joanna Bridger (Uxbridge, United Kingdom) Jacqueline Capeau (Paris, France) Annachiara De Sandre-Giovanna (Marseille, France) Roland Foisner (Vienna, Austria) (scientific coordinator) Camilla Giammarini (DIATHEVA, Fano, Italy) Yosef Gruenbaum (Jerusalem, Israel) Joaquin Guinea (ZFBioLabs, Tres Cantos, Spain) Harald Herrmann (Heidelberg, Germany) Chris Hutchison (Durham,United Kingdom) Giovanna Lattanzi (Bolgona, Italy) Nicolas Lévy (Marseille, France) Nadir Maraldi (Bologna, Italy) Olga Mayans (Basel, Switzerland) Giuseppe Novelli (Rome, Italy) Brigitte Rohner (punkt, Vienna, Austria) Manfred Wehnert (Greifswald, Germany) Andoni Urtizberea (ENMC, Baarn, The Netherland) Patricia Gosling (ENMC, Baarn, The Netherland) Rose-Marie van der Voort (ENMC, Baarn, The Netherland) Annelies Zittersteijn (ENMC, Baarn, The Netherland) Acknowledgements This workshop was made possible thanks to the financial support of the European Neuromuscular Centre (ENMC) and ENMC main sponsors: Association Française contre les Myopathies (France), Deutsche Gesellschaft für Muskelkranke (Germany), Telethon Foundation (Italy), Muscular Dystrophy Campaign (UK), Muskelvindfonden (Denmark), Prinses Beatrix Fonds (The Netherlands), Schweizerische Stiftung für die Erforschung der Muskelkrankheiten (Switzerland), Österreichische Muskelforschung (Austria), Vereniging Spierziekten Nederland (The Netherlands), Associacion Espanola contra las Enfermedades Neuromusculares (Spain). 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Max F. Perutz Laboratories, Medical University of Vienna, Dr.Bohr-Gasse 9, A-1030 Vienna, Austria  Corresponding author. Tel.: +43 1 4277 61680; fax: +43 1 4277 9616.
PII: S0960-8966(07)00138-1 doi:10.1016/j.nmd.2007.04.003 © 2007 Elsevier B.V. All rights reserved. | |
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