The “Aging, Prenylation and Cancer” team, gathers 4 groups with distinct but tightly linked research axes oriented on aging, cancer, spermatogenesis and networks/systems biology.


The involvement of aberrantly accumulated or activated prenylated proteins (with Farnesyl or Geranyl‐geranyl hydrophobic C terminus anchors) in all these disease categories (genetically determined premature aging (progeroid) syndromes (PS) and lipodystrophies, cancer, human physiological and pathological spermatogenesis) serves as a focus and common denominator of our scientific research strategies. The department “Aging, Prenylation & Cancer” is unique in France and will increase collaborations with French, EU and international teams currently working on premature aging, laminopathies and prenylated proteins-associated cancers with the major aim of developing translational research.

We propose to use the exploration of both in vitro and in vivo models:
1) to further delineate and enlarge the clinical spectrum of diseases characterized by premature aging/ lipodystrophy/cancer development/altered human spermiogenesis, possibly associated to dysfunction of prenylated proteins or functional interactors;
2) to dissect the molecular mechanisms underlying these syndromes, allowing to identify therapeutic targets;
3) to develop pre-clinical proofs of concepts;
4) to extrapolate the generated knowledge aiming to improve healthy aging, by verifying whether the identified mechanisms apply to similar “natural” aging-associated morbidities;
5) to improve our knowledge on cancers involving prenylated proteins’ dysfunction towards identifying therapeutic targets and ameliorate patients’ healthcare;
6) to launch novel therapeutic trials.

The main long-term objective of the team is indeed the transposition of our discoveries to address and implement care in premature aging syndromes, age-related morbidities, natural aging and cancers. A strategy combining several approaches will lead to the pursuit of the following objectives in the field of “Prenylopathies”.



Group leader: Nicolas Lévy

Since we and others discovered the involvement of the LMNA gene encoding the nuclear proteins Lamins A/C, in Hutchinson-Gilford Progeria Syndrome (OMIM #176670), one of the best known premature aging syndromes (De Sandre-Giovannoli et al., Science 2003), our team focuses on translational research on premature aging (progeroid) syndromes (PS), nuclear protein-linked lipodystrophies, as well as other premature aging diseases, with or without an identified molecular basis. Our research aims to identify novel genes involved in these syndromes, increase our understanding of their pathophysiological mechanisms and to develop new therapeutic approaches using patients’ cell lines or mouse models as our main preclinical tools.


PS are a group of rare genetic disorders characterized by many clinical features that mimic those associated to physiological aging. Many PS share the dysfunction of a prenylated protein. This is the case in Hutchinson-Gilford Progeria Syndrome (HGPS) and related PS, where prenylated progerin or prelamin A aberrantly accumulate in cells’ nuclei, exerting multiple toxic effects and ultimately leading to the systemic severe phenotypes observed in patients. Besides, several other PS have been discovered as being caused by activating mutations in genes encoding permanently prenylated proteins of the RAS‐MAPK pathways. Among these “RASopathies”, research on Costello syndrome, due to H-RAS mutations, will be part of this project. Finally, several lines of evidence suggest that progerin production may also be involved in natural aging pathomechanisms.

Our research has focused until now on the following axes:

a. Extend the clinical spectrum of syndromes associated with prelamin A deficient processing.
We identified several novel or related syndromes mainly characterized by premature aging 7-25 or lipodystrophy / metabolic syndrome 9, 26 linked to mutations of LMNA or functionally related genes; as well as previously undiscovered genetic associations 10.

b. Produce in vitro and in vivo models for studying rare progeroid syndromes
A large panel of data and primary fibroblast cell lines from children affected with typical Progeria or atypical PS, and progeroid RASopathies have been collected through national and international collaborations and are stored in the Biological Resources Center (CRB-TAC), at La Timone hospital, Marseille. Human iPS cell lines (hiPSC) have also been derived and used to study the pathophysiology of the syndrome 27 or compare ongoing or proposed treatments 28. Primary endothelial cells and progenitors issued from human umbilical vein or cord blood were also used as in vitro models to study HGPS pathophysiology 29. Importantly, in collaboration with Pr Lopez-Otin in Oviedo, we generated the mouse model of progeria which most closely mimics the human disease (Knock-In LmnaG609G/G609G) by reproducing the same aberrant splicing mechanism leading to progerin production 30. Additionally, we are involved in a consortium with the mouse clinical institute and the medical genetics team in Bordeaux, to explore a KI model of CS carrying the most common H-RAS p.G12S mutation, based on a project  funded by the ANR (Cf. Appendix 7).

 c. Identify disease mechanisms in progeroid syndromes

  • We demonstrated a common toxic pathway involving prenylated prelamin A accumulation in many PS ranging from restrictive dermopathy and MAD-B to HGPS-like syndromes 8, 12, 24, 25, 31-36.
  • We showed that the microRNA miR‐9 negatively controls lamin A and progerin expression in HGPS­hiPSC derived neural cells 27, 28, having a protective effect on the patients’ central nervous system, which is clinically spared.
  • A miRNome analysis by qRT-PCR on dermal fibroblasts of 5 HGPS patients and 5 healthy individuals at early and late passages, allowed the identification of 29 deregulated miRNAs (15 overexpressed, 14 underexpressed; Frankel et al., publication in preparation). Based on these in vitro results, the potential benefit of miRNA-based therapeutic approaches (antagomiRs or mimics) in HGPS is under evaluation.
  • We contributed to scientific reviews on progeroid laminopathies and related syndromes 7, 8, 37
  • We reported H­RAS mutations in CS patients, confirming the involvement of the activated prenylated RAS proteins 38 in RASopathies, shown to trigger senescence in vitro 39.

d. Establish preclinical proofs of principle for therapeutic approaches and launch clinical trials

  • We demonstrated the synergistic effect of pravastatin (statin) and zoledronate (N-BisPhosphonate) (ZoPra) and its effectiveness in reducing prenylation and rescuing HGPS cells defects and progeroid phenotypes in Zmpste24-/- mice 40.
  • this preclinical work allowed our clinical team to design, and conduct a phase II therapeutic trial (ClinicalTrials.gov, NCT00731016) using zoledronate and pravastatin to evaluate its safety and efficacy in 12 HGPS patients included for 3.5 years each, with partially positive results on primary and secondary endpoints and without severe adverse effects (De Sandre‐Giovannoli, Sigaudy et al, submitted). An Orphan drug designation for this drug combination, “ZoPra”, was also obtained from EMA for progeria, under patent with an exclusive licence to ProGeLife, a spin-off of our academic team, cf. Appendix 6.
  • We showed an efficient reduction of progerin production in vitro at the mRNA and protein levels and phenotypic rescue in the LmnaG609G/G609G mice, using systemic antisense oligonucleotide (AON) treatment 41, providing the first preclinical proof of principle in vivo of the efficacy of this novel and promising approach.
  • We further provided a preclinical proof of principle for the use of a similar, but personalized antisense treatment in patients affected with HGPS-like and type B Mandibuloacral Dysplasia syndromes 42, who may therefore also be eligible for inclusion in a therapeutic trial based on this approach, together with classical HGPS patients.
  • We collaborated in preclinical studies using high-throughput screening of already marketed compounds with HGPS-derived iPS-MSC, leading to the identification of potential novel drugs 43, 44 or comparisons of the efficacy of treatments being tested in clinical trials 28.

Importantly, we recently identified that a specific class of proteasome inhibitors, including MG132, are able to reduce progerin levels by inducing both its degradation through autophagy and inhibition of its production by mRNA splicing modulation45. These findings pave the way for the development of a novel promising class of drugs for the treatment of patients affected with Hutchinson-Gilford Progeria and related syndromes. They may as well find larger applications in diseases involving the accumulation of prenylated proteins or natural aging. This discovery was patented and is co-exploited by ProGeLife (co-owner) and SATT-Sud Est (SATT-SE).

Our future research will be developed on similar strategies:

  • Pursue the data and biological samples’ collection from patients affected with PS and RASopathies stored in the labelled Biological Resource Center (CRB TAC), Department of Medical Genetics, Timone Hospital of Marseille; by establishing iPSC lines which are undergoing differentiation in cell lines of interest, depending on the patient’s phenotypes (collaboration with X. Nissan, iSTEM and F. Magdinier, U910 iPSC platform), by developing future CRISPR mutated iPS cell lines with mutations of interest. Our center also participates to the National registry “OPALE” (https://epidemiologie-france.aviesan.fr/epidemiologie-france/fiches/observatoire-des-patients-atteints-de-laminopathies-et-emerinopathies), collecting longitudinal informations on patients affected with laminopathies and carrying mutations of the LMNA gene.
  • Identify further biomarkers and pathophysiological pathways of premature aging: To dissect the mechanisms of aging caused by dysfunctions of prenylated proteins, we will combine OMICs data (genome, transcriptome/miRNome, proteome, and microbiome), with bioinformatics and systems’ biology interpretation tools. We aim to identify disease biomarkers, pro-and anti-aging factors, and druggable targets using primary fibroblasts from HGPS, Atypical Progeroid Syndromes (APS) due to LMNA mutations, CS patients and age and sex-matched controls; fibroblast-derived hiPSCs cells; 2) iPS-derived differentiated cells (coll. F. Magdinier) from selected APS patients and compared to similar age-matched HGPS and control cells; 3) mouse tissues or tail-tip fibroblast cultures of HGPS (LmnaG609G/G609G) and CS (HrasG12S/G12S) models and controls (wild type mice from the same crosses).
  • Identify and validate Proof-of-Concepts for molecules exhibiting a therapeutic potential in cellular and animal models:  we propose a multi-step, sequential translational approach from patients’ cells explorations to the preclinical validation of compounds in order to advance with solid bases towards novel clinical trials. Both pharmacologic and gene therapy approaches are under study in the team. Concerning the first approach, we recently identified that MG132 and other aldehyde compounds of the same class of proteasome inhibitors are able to dramatically reduce progerin intranuclear levels and ameliorate several disease parameters in HGPS patients’ cell lines. These molecules act by preventing progerin synthesis and increasing progerin degradation both in vitro (HGPS fibroblasts, iPS-MSC and iPS-VSMC from HGPS iPSC) and in vivo (muscles of LmnaG609G/G609G mice)45. Preliminary in vivo pilot studies indicate that the systemic administration of MG132 will require the formulation of a novel galenic form to increase its half-life: this work will be developed in collaboration with industrial and academic partners.In this research axis, the different compounds that are found efficient alone will be tested in combination. Their ability to improve classical disease biomarkers in vitro will be evaluated, with dose-response studies. This study will be completed in vivo, exploring: the drug pharmacokinetics, safety/toxicity, the effects on progerin levels and OMICS studies to validate drug activity and to search for side-effects.
    Interestingly, since progerin has been shown to accumulate in cells’ nuclei during natural aging 3, the proposed research on HGPS and related syndromes may have spinoffs in the field of natural aging.
  • Identification of novel genes involved in premature aging syndromes:  Efforts will be continued towards: 1) identifying novel causal genes in patients affected with sporadic PS or lipodystrophy syndromes of unknown origin (ex. Wiedemann­Rautenstrauch, Hallermann-Streiff syndromes, atypical progeroid syndromes…), and genomic modulators that account for phenotypic variability in PS with extreme phenotypes
  • Functional characterization of pathogenic variants in Lamin A and LINC complex proteins in nuclear protein-linked lipodystrophies: Recent studies have revealed the important role played by the nuclear envelope (NE) in the cell response to various external environmental constraints. In particular, A-type Lamins and proteins of the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex are key actors of nucleo-cytoskeletal coupling, playing a role in nuclear signal mechanotransduction 46. We’ll use patients’ cells to investigate the relationship between NE and LINC complex proteins and pathologies.

Group leader: Michael Mitchell

 

Group Web Page

In the age of Assisted Reproductive Technology (ART), where defective gametogenesis is no longer a barrier to procreation, it is crucial to understand how the genome is normally processed in germ cells, detect cases where processing is abnormal and determine the consequences of anomalies for genome stability. We will thus characterize the nuclear lamina during human spermatogenesis, and discover proteins required for nuclear remodelling by searching for genetic causes of abnormal sperm head development (teratozoospermia) and the creation of specific knockout mouse models. Our group has a strong clinical component and enjoys close collaborations with La Conception and La Timone Hospital sites: the Reproductive Biology Laboratory, Centre for the study and conservation of human oocytes and sperm (CECOS, directed by C. Metzler-Guillemain), the Molecular Genetics Laboratory in the Department of Medical Genetics and the Germethèque, a labelled Biobank. We also have a collection of normal testicular material, from patients with brain death, deposited in the Germethèque Biobank and authorized by the Biomedicine Agency (ABM).

 

Group leader: Sylviane Olschwang

The cancer project focuses on the identification of genetic variants that contribute either to increase the risk of digestive cancer or to aggravate their evolution, according to 2 main axes:

  • Pharmacogenetics and therapeutic evaluation in digestive oncology
  • Hereditary predispositions to digestive cancers

A third axis "genetics of sarcomas and related tumors" was initiated this year
Joining Nicolas Lévy's team, the research projects have been re-centered on tumors impairing pathways involved in premature aging, mainly RAS and TGFB, to identify potential therapeutic targets useful in in both conditions. The pancreatic cancerogenesis of mucinous cysts has been chosen as study model.

Past results

The projects of the group focused on the study of gastrointestinal tumorigenesis mechanisms to identify genetic variations or mutations that contribute to or increase their risk, or impact their evolution. The clinical objective was to better integrate into medical practice DNA analyses, which take a special place in various aspects of oncology, prevention, early diagnosis and therapeutic evaluation. In the past, we described the genetic alterations responsible for major genetic predispositions to digestive cancer and their relationship with the main phenotypic characteristics. The molecular analyses have been progressively transferred to hospital laboratories and integrated to the medical care of patients. We coordinate the data collection of germ line mutations identified in the French labeled laboratories in national mutations databases and permanently implement these LSDBs with functional data allowing variants classification. Furthermore, the study of somatic genetic alterations in colorectal cancer, to which we contributed, identified two alternative pathways of colon cancer, linked to different prognostic risks. The allelic loss frequencies and the complexity of their associations, as well as the difficulty of finding a major event in tumor progression prompted us to undertake a comprehensive genomic characterization of colorectal cancer combining genome and transcriptome analysis. The direct responsibility of the WNT pathway via the APC gene appeared the most probable hypothesis that was specifically explored 59. To document the existence of genes predisposing to the development of metastases based on genotype-phenotype associations, we set up a national group of clinicians and researchers to collect such case-control series and were able to describe the first locus involved in the metastatic process 60, where a non-coding RNA was then identified by another group 61, 62.
An interface contract with the Institut Paoli-Calmettes allowed us to develop a regional laboratory that contributes to the diagnostic and therapeutic evaluation of cancer.

Project

Joining Nicolas Lévy's team, the group will re-direct its research projects on tumors impairing pathways also involved in premature aging, mainly RAS and TGFB, to identify potential therapeutic targets in pathways involved in both conditions. Since 2006, targeted therapies have been developed to improve solid tumors treatment, like anti-EGFR and Tyrosine kinase inhibitors that are now used in metastatic colorectal and lung cancers. Anti-EGFRs have been first demonstrated as ineffective in case of K-RAS gene activation, and their use has been restricted to tumors without K-RAS somatic mutations. Subsequently, a systematic molecular analysis of tumor cells has been introduced in cancer patients’ management, and the EGFR pathway has been more extensively characterized to document the mechanisms of drug resistance. Similar observations have been made in cases of N-RAS, BRAF or PTEN mutations as examples. Drugs targeting other steps of the pathway have been tested and the use of prenylation inhibitors revealed promising directions to manage devastating tumors such pancreatic, lung and ovarian cancers 63, 64 for reviews. The use of xanthohumol, a prenylated chalcone, is able to induce cell cycle arrest and apoptosis by inhibiting phosphorylation of STAT3, together with expression of downstream targets cyclin D1 and survivin in cell lines and xenografts of pancreatic cancer 65. Combined geranylgeranyltransferase 1 and farnesyltransferase inhibitors liposomal delivery induces G1 cycle cell arrest by p21CIP1/WAF1 in human pancreatic and lung cancer cell lines 66. Zoledronic acid on lung cancer and melanoma cells with NRAS mutation inhibited prenylation, supressing downstream RAS and EGFR signaling. This effect has been reversed using geranylgeraniol and farnesol, confirming the specific prenylation inhibition 67, 68. In combination with paclitaxel, which showed promising results in pancreatic cancer, synergistic effects could be obtained. Blocking the mevalonate pathway with statins also shows interference with post-translational modification of KRAS inducing antiproliferative phenotype of ovarian cancer cells from xenografts 69, suppression of proliferation linked to endocrine resistance resulting from the accumulation of senescent cells after radio/chemotherapy of breast and prostate cancer 70, 71. Isoprenoid biosynthetic pathway inhibitors also showed Rap1A alteration in metastatic prostate cancer cells 72.

Pancreatic cancer is one of the most lethal human cancers, exhibiting RAS pathway activation in more than 80% of cases. The unique treatment consists in chemotherapy based on 5FU or gemcitabine solely or in combination with irinotecan and/or oxaliplatine, adjuvant to surgery in less than 20% of cases, often used as palliative. Clinical trials currently introduce other molecules without any positive result. Pancreatic cancer also takes part of the tumor spectrum of several genetic disorders highly predisposing to cancer (BRCA, Lynch, Peutz-Jeghers, Cowden, Von Hippel Lindau syndromes as the most frequent). Precancerous lesions have been described, particularly pancreatic cysts with mucinous component, known at high risk for cancer. These tumors were retained as an interesting model to extensively study the EGFR/RAS pathway, looking for targetable modifications. A collaborative consortium has been set up in Marseille, including all interventional digestive endoscopy units and the corresponding surgical departments (AP-HM hospitals Timone and Nord, St-Joseph hospital, European Hospital, Institut Paoli-Calmettes), and two expert centers in Lyon (Mermoz hospital) and Paris (Les Peupliers hospital). We plan to collect samples of cystic fluid and analyze“circulating” DNA from surrounding epithelial cells. As blood circulating tumor cells showed their ability to reveal molecular alterations as cancer diagnostics or recurrence markers, tumor cells are initially present in cystic fluids and can be collected for further molecular investigations 73, 74.

A pilot study has just been funded, which will test the feasibility of a systematic approach comparing the molecular profiles of cysts in pre-operative echoendoscopic biopsies and per-operative samples of 10 patients, thus validating the preoperative approach as applicable to a larger series, as echoendoscopic biopsies are systematically performed before surgery to confirm the clinical indication of pancreatectomy. Sample processing and NGS sequencing will be done within U910. Nucleic acids will be extracted and sequenced on a panel of 70 genes involved in pancreatic tumorigenesis and targeting the RAS signaling pathway, MAPK, AKT, JAK-STAT signaling pathway, WNT, TGFB, TP53 and repair BRCA, ATM. The selected sequencing technology (HaloPlexHS®, Agilent), through the incorporation of random nucleic acid sequences (10 nucleotides) during the libraries preparation, enables detection of alleles present in a 1% proportion. This new technical approach that combines high sensitivity and specificity is also compatible with degraded DNA and/or small amounts (less than 50 ng). It therefore appears as an appropriate technique for this type of samples with an expected important degradation and nucleic clonal heterogeneity. Bioinformatics analysis will detect somatic variations and define their allelic frequency as well as CNVs. A comparison of the molecular profiles of pre- and post-operative samples will be performed, then faced with the pathologic and biological characteristics. The identification of a molecular profile indicating a precancerous condition would be helpful for the surgical decision, which consists in a (cephalic) pancreatectomy, now performed twice more than a posteriori required. The characterization of the very early recurrent molecular alterations would also be helpful to refine targeted therapies, and to test cell models exhibiting similar pathways disorders.
At the same time, the group, in collaboration with French clinical oncogenetics units, is currently collecting families with aggregation of breast/pancreatic cancer without known germline alterations to define through exomes analyses a set of candidate genes that could be involved in such predispositions. Variations identified by this approach will be compared to those enlightened in the previous part, to document the genetic alterations responsible for the very early steps of pancreatic tumorigenesis.
Finally, as multichemotherapy is currently the single therapeutic approach in pancreatic cancer, the group drives pharmacogenetics studies to possibly add new parameters useful in dosage adjustment in collaboration with the oncology units of the university hospital. This year, clinical files of 98 patients have been registered and 87 have been genotyped on 1636 SNPs of 231 genes using the DMET chip (Affymetrix). Associations with toxicity have been identified for genes participating to phases I and II metabolism enzymes and transporters. The set of data will be extended, genotyping 279 patients included in the national clinical trial PRODIGE35 in collaboration with the Fédération Française de Cancérologie Digestive (FFCD) to validate primary results.

 

Group leader: Anaïs Baudot

 

Group Web Page

The group Networks and Systems Biology for Diseases focuses on untangling the genotype-phenotype relationships of human disorders. Disease complexity is the consequence of the intricate cellular functioning of genes and proteins. Indeed, biological molecules do not act alone, but rather interact with each other to perform their functions in protein complexes, signalling pathways or metabolic reactions. The disease phenotypes are thus resulting not from perturbations of isolated genes or proteins, but of complex networks of molecular interactions.
In this context, thanks to network modeling and large-scale interactome and -omics mining, our group studies genes and proteins in their cellular contexts, towards a better understanding of their perturbations in diseases. We further investigate the relationships between different diseases, in particular disease comorbidities, and aim to improve diagnostic and therapeutic predictions.

 

 

Valdeolivas, A.  et al. 2018

Random Walk with Restart on Multiplex and Heterogeneous Biological Networks

Motivation: Recent years have witnessed an exponential growth in the number of identified interactions between biological molecules. These interactions are usually represented as large and complex...
Bioinformatics - issue: - volume: - pages: 1-9.

Paci, M.  et al. 2018

The involvement of the nuclear lamina in human and rodent spermiogenesis: a systematic review

The nuclear lamina (NL) is a filamentous protein meshwork, composed essentially of lamins, situated between the inner nuclear membrane and the chromatin. The NL is a component of the nuclear envelope,...
Basic Clin Androl - issue: - volume: 28 - pages: 7.

Barthélémy, F.  et al. 2018

Muscle Cells Fix Breaches by Orchestrating a Membrane Repair Ballet

Skeletal muscle undergoes many micro-membrane lesions at physiological state. Based on their sizes and magnitude these lesions are repaired via different complexes on a specific spatio-temporal...
J Neuromuscul Dis - issue: 1 - volume: 5 - pages: 21-28.

Guinde, J.  et al. 2018

Lamins in Lung Cancer: Biomarkers and Key Factors for Disease Progression through miR-9 Regulation?

Lung cancer represents the primary cause of cancer death in the world. Malignant cells identification and characterization are crucial for the diagnosis and management of patients with primary or...
Cells - issue: 7 - volume: 7 - pages: .

Lo Cicero, A.  et al. 2018

Pathological modelling of pigmentation disorders associated with Hutchinson-Gilford Progeria Syndrome (HGPS) revealed an impaired melanogenesis pathway in iPS-derived melanocytes

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic disorder that leads to premature aging. In this study, we used induced pluripotent stem cells to investigate the hypopigmentation...
Sci Rep - issue: 1 - volume: 8 - pages: 9112.

Bourgeois, P.  et al. 2018

Tricho-Hepato-Enteric Syndrome mutation update: Mutations spectrum of TTC37 and SKIV2L, clinical analysis and future prospects

Tricho-Hepato-Enteric syndrome (THES) is a very rare autosomal recessive syndromic enteropathy caused by mutations of either TTC37 or SKIV2L genes. Very little is known of these two gene products in...
Hum. Mutat. - issue: 6 - volume: 39 - pages: 774-789.

Frankel, D.  et al. 2018

MicroRNAs in hereditary and sporadic premature aging syndromes and other laminopathies

Hereditary and sporadic laminopathies are caused by mutations in genes encoding lamins, their partners, or the metalloprotease ZMPSTE24/FACE1. Depending on the clinical phenotype, they are classified...
Aging Cell - issue: - volume: - pages: e12766.

Esteve, C.  et al. 2018

Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility

Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with syndromic manifestations. Here, we have studied four affected people in three...
Am. J. Hum. Genet. - issue: 3 - volume: 102 - pages: 364-374.

Harhouri, K.  et al. 2018

An overview of treatment strategies for Hutchinson-Gilford Progeria syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is a sporadic, autosomal dominant disorder characterized by premature and accelerated aging symptoms leading to death at the mean age of 14.6 years usually...
Nucleus - issue: 1 - volume: 9 - pages: 246-257.

Elkhatib, RA.  et al. 2017

LEM-domain proteins are lost during human spermiogenesis but BAF and BAF-L persist

During spermiogenesis the spermatid nucleus is elongated, and dramatically reduced in size with protamines replacing histones to produce a highly compacted chromatin. After fertilisation, this process...
Reproduction - issue: 4 - volume: 154 - pages: 387-401.

Kaspi, E.  et al. 2017

Low lamin A expression in lung adenocarcinoma cells from pleural effusions is a pejorative factor associated with high number of metastatic sites and poor Performance status

The type V intermediate filament lamins are the principal components of the nuclear matrix, including the nuclear lamina. Lamins are divided into A-type and B-type, which are encoded by three genes,...
PLoS ONE - issue: 8 - volume: 12 - pages: e0183136.

Harhouri, K.  et al. 2017

MG132-induced progerin clearance is mediated by autophagy activation and splicing regulation

Hutchinson-Gilford progeria syndrome (HGPS) is a lethal premature and accelerated aging disease caused by a de novo point mutation in LMNA encoding A-type lamins. Progerin, a truncated and toxic...
EMBO Mol Med - issue: 9 - volume: 9 - pages: 1294-1313.

Paci, M.  et al. 2017

Abnormal retention of nuclear lamina and disorganization of chromatin-related proteins in spermatozoa from DPY19L2-deleted globozoospermic patients

The aim of this study was to characterize the nuclear lamina (NL) and lamin chromatin-partners in spermatozoa from four DPY19L2-deleted globozoospermic patients. We tested for spermatid transcripts...
Reprod. Biomed. Online - issue: 5 - volume: 35 - pages: 562-570.

Cerino, M.  et al. 2017

Genetic Characterization of a French Cohort of GNE-mutation negative inclusion body myopathy patients with exome sequencing

INTRODUCTION: Hereditary inclusion body myopathy (hIBM) refers to a group of clinically and genetically heterogeneous diseases. The overlapping histochemical features of hIBM with other genetic...
Muscle Nerve - issue: 5 - volume: 56 - pages: 993-997.

Jallades, L.  et al. 2017

Exome sequencing identifies recurrent BCOR alterations and the absence of KLF2, TNFAIP3 and MYD88 mutations in splenic diffuse red pulp small B-cell lymphoma

Splenic diffuse red pulp lymphoma is an indolent small B-cell lymphoma recognized as a provisional entity in the World Health Organization 2008 classification. Its precise relationship to other...
Haematologica - issue: 10 - volume: 102 - pages: 1758-1766.

Bal, E.  et al. 2017

Mutations in ACTRT1 and its enhancer RNA elements lead to aberrant activation of Hedgehog signaling in inherited and sporadic basal cell carcinomas

Basal cell carcinoma (BCC), the most common human cancer, results from aberrant activation of the Hedgehog signaling pathway. Although most cases of BCC are sporadic, some forms are inherited, such as...
Nat. Med. - issue: 10 - volume: 23 - pages: 1226-1233.

Nguyen, K.  et al. 2017

Molecular combing reveals complex 4q35 rearrangements in Facioscapulohumeral dystrophy

Facioscapulohumeral dystrophy (FSHD), one of the most common hereditary neuromuscular disorders, is associated with a complex combination of genetic variations at the subtelomeric 4q35 locus. As...
Hum. Mutat. - issue: 10 - volume: 38 - pages: 1432-1441.

Elkhatib, RA.  et al. 2017

Homozygous deletion of SUN5 in three men with decapitated spermatozoa

A recent study of 17 men with decapitated spermatozoa found that 8 carried two rare SUN5 alleles, and concluded that loss of SUN5 function causes the acephalic spermatozoa syndrome. Consistent with...
Hum. Mol. Genet. - issue: 16 - volume: 26 - pages: 3167-3171.

Elouej, S.  et al. 2017

Exome sequencing reveals a de novo POLD1 mutation causing phenotypic variability in mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL)

Background. Mandibular hypoplasia, deafness, progeroid features; and lipodystrophy syndrome (MDPL) is an autosomal dominant systemic disorder characterized by prominent loss of subcutaneous fat, a...
Metab.-Clin. Exp. - issue: - volume: 71 - pages: 213-225.

Lacoste, C.  et al. 2017

Next-generation DNA sequencing in clinical diagnostics

The advent of next generation sequencing (NGS) technologies is so scale-changing that it modifies molecular diagnostics indications and induces laboratories to rethink their diagnostic strategies,...
Arch. Pediatr. - issue: 4 - volume: 24 - pages: 373-383.

Gordon, CT.  et al. 2017

De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense...
Nature Genet. - issue: 2 - volume: 49 - pages: 249-255.

Ittel, A.  et al. 2016

Molecular combing: A new tool in diagnosing leukemia

BACKGROUND: According to the World Health Organization (WHO), recurrent cytogenetic abnormalities define many specific groups of hematopoietic tumors of acute myeloid and lymphoblastic leukemia, and...
Cancer Biomark. - issue: 4 - volume: 17 - pages: 405-409.

Egesipe, A.  et al. 2016

Metformin decreases progerin expression and alleviates pathological defects of Hutchinson-Gilford progeria syndrome cells

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder that causes systemic accelerated aging in children. This syndrome is due to a mutation in the LMNA gene that leads to the...
npj Aging Mech. Dis. - issue: - volume: 2 - pages: UNSP 16026.

Soria-Valles, C.  et al. 2016

Novel LMNA mutations cause an aggressive atypical neonatal progeria without progerin accumulation

BACKGROUND: Progeroid syndromes are genetic disorders that recapitulate some phenotypes of physiological ageing. Classical progerias, such as Hutchinson-Gilford progeria syndrome (HGPS), are generally...
J. Med. Genet. - issue: 11 - volume: 53 - pages: 776-785.

Lo Cicero, A.  et al. 2016

A High Throughput Phenotypic Screening reveals compounds that counteract premature osteogenic differentiation of HGPS iPS-derived mesenchymal stem cells

Hutchinson-Gilford progeria syndrome (HGPS) is a rare fatal genetic disorder that causes systemic accelerated aging in children. Thanks to the pluripotency and self-renewal properties of induced...
Sci Rep - issue: - volume: 6 - pages: 34798.

Bevilacqua, J.  et al. 2016

Calpainopathy in Chile, first cases reported


Neuromusc. Disord. - issue: - volume: 26 - pages: S91-S91.

Gaillard, M.  et al. 2016

Segregation between SMCHD1 mutation, D4Z4 hypomethylation and Facio-Scapulo-Humeral Dystrophy: a case report

BACKGROUND: The main form of Facio-Scapulo-Humeral muscular Dystrophy is linked to copy number reduction of the 4q D4Z4 macrosatellite (FSHD1). In 5 % of cases, FSHD phenotype appears in the absence...
BMC Med. Genet. - issue: 1 - volume: 17 - pages: 66.

Harhouri, K.  et al. 2016

Antisense-Based Progerin Downregulation in HGPS-Like Patients' Cells

Progeroid laminopathies, including Hutchinson-Gilford Progeria Syndrome (HGPS, OMIM #176670), are premature and accelerated aging diseases caused by defects in nuclear A-type Lamins. Most HGPS...
Cells - issue: 3 - volume: 5 - pages: .

Galant, D.  et al. 2016

A Heterozygous ZMPSTE24 Mutation Associated with Severe Metabolic Syndrome, Ectopic Fat Accumulation, and Dilated Cardiomyopathy

ZMPSTE24 encodes the only metalloprotease, which transforms prelamin into mature lamin A. Up to now, mutations in ZMPSTE24 have been linked to Restrictive Dermopathy (RD), Progeria or Mandibulo-Acral...
Cells - issue: 2 - volume: 5 - pages: 21.

Salgado, D.  et al. 2016

UMD-Predictor: A High-Throughput Sequencing Compliant System for Pathogenicity Prediction of any Human cDNA Substitution

Whole-exome sequencing (WES) is increasingly applied to research and clinical diagnosis of human diseases. It typically results in large amounts of genetic variations. Depending on the mode of...
Hum. Mutat. - issue: 5 - volume: 37 - pages: 439-446.

Di Meglio, C.  et al. 2016

Clinical and allelic heterogeneity in a pediatric cohort of 11 patients carrying MFN2 mutation

INTRODUCTION: The Mitofusin 2 gene (MFN2), which encodes a mitochondrial membrane protein, is known to be the first cause of autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2) with early...
Brain Dev. - issue: 5 - volume: 38 - pages: 498-506.

Ambrosi, P.  et al. 2016

A novel overlapping phenotype characterized by lipodystrophy, mandibular dysplasia, and dilated cardiomyopathy associated with a new mutation in the LMNA gene


Int. J. Cardiol. - issue: - volume: 209 - pages: 317-318.

Lacoste, C.  et al. 2016

Coverage analysis of lists of genes involved in heterogeneous genetic diseases following benchtop exome sequencing using the ion proton


J. Genet. - issue: 1 - volume: 95 - pages: 203-208.

Nishikawa, A.  et al. 2016

Respiratory and Cardiac Function in Japanese Patients with Dysferlinopathy

Introduction: We retrospectively reviewed respiratory and cardiac function in patients with dysferlinopathy, including 2 autopsy cases with respiratory dysfunction. Methods: Subjects included 48...
Muscle Nerve - issue: 3 - volume: 53 - pages: 394-401.

Sevy, A.  et al. 2016

Improving molecular diagnosis of distal myopathies by targeted next-generation sequencing


J. Neurol. Neurosurg. Psychiatry - issue: 3 - volume: 87 - pages: 340-U116.

Blondel, S.  et al. 2016

Drug screening on Hutchinson Gilford progeria pluripotent stem cells reveals aminopyrimidines as new modulators of farnesylation

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by a dramatic appearance of premature aging. HGPS is due to a single-base substitution in exon 11 of the LMNA gene...
Cell Death Dis. - issue: - volume: 7 - pages: e2105.

Woudt, L.  et al. 2016

Toward an Objective Measure of Functional Disability in Dysferlinopathy

Introduction: Understanding the natural history of dysferlinopathy is essential to design and quantify novel therapeutic protocols. Our aim in this study was to assess, clinically and functionally, a...
Muscle Nerve - issue: 1 - volume: 53 - pages: 49-57.

Fatehi, F.  et al. 2015

Dysferlinopathy in Iran: Clinical and genetic report

Background: Dysferlinopathy is caused by a very wide range of autosomal recessively inherited mutations of the Dysferlin gene. It causes a spectrum of muscle diseases including limb-girdle muscular...
J. Neurol. Sci. - issue: 1-2 - volume: 359 - pages: 256-259.

Vodopiutz, J.  et al. 2015

WDR73 Mutations Cause Infantile Neurodegeneration and Variable Glomerular Kidney Disease

Infantile-onset cerebellar atrophy (CA) is a clinically and genetically heterogeneous trait. Galloway-Mowat syndrome (GMS) is a rare autosomal recessive disease, characterized by microcephaly with...
Hum. Mutat. - issue: 11 - volume: 36 - pages: 1021-1028.

Ben Yaou, R.  et al. 2015

First italo-french meeting on laminopathies and other pathologies related to the nuclear envelope


M S-Med. Sci. - issue: - volume: 31 - pages: 39-40.

Barthelemy, F.  et al. 2015

Truncated prelamin A expression in HGPS-like patients: a transcriptional study

Premature aging syndromes are rare genetic disorders mimicking clinical and molecular features of aging. A recently identified group of premature aging syndromes is linked to mutation of the LMNA gene...
Eur. J. Hum. Genet. - issue: 8 - volume: 23 - pages: 1051-1061.

Gorokhova, S.  et al. 2015

Clinical massively parallel sequencing for the diagnosis of myopathies

Massively parallel sequencing, otherwise known as high-throughput or next-generation sequencing, is rapidly gaining wide use in clinical practice due to possibility of simultaneous exploration of...
Rev. Neurol. - issue: 6-7 - volume: 171 - pages: 558-571.

Kergourlay, V.  et al. 2015

Comment on: A novel dysferlin-mutant pseudoexon bypassed with antisense oligonucleotides


Ann. Clin. Transl. Neurol. - issue: 7 - volume: 2 - pages: 783-784.

Nectoux, J.  et al. 2015

Detection of TRIM32 deletions in LGMD patients analyzed by a combined strategy of CGH array and massively parallel sequencing

Defects in TRIM32 were reported in limb-girdle muscular dystrophy type 2H (LGMD2H), sarcotubular myopathies (STM) and in Bardet-Biedl syndrome. Few cases have been described to date in LGMD2H/STM, but...
Eur. J. Hum. Genet. - issue: 7 - volume: 23 - pages: 929-934.

Jobling, RK.  et al. 2015

PMPCA mutations cause abnormal mitochondrial protein processing in patients with non-progressive cerebellar ataxia

Non-progressive cerebellar ataxias are a rare group of disorders that comprise approximately 10% of static infantile encephalopathies. We report the identification of mutations in PMPCA in 17 patients...
Brain - issue: - volume: 138 - pages: 1505-1517.

Puppo, F.  et al. 2015

Identification of Variants in the 4q35 Gene FAT1 in Patients with a Facioscapulohumeral Dystrophy-Like Phenotype

Facioscapulohumeralmuscular dystrophy (FSHD) is linked to copy-number reduction (N<10) of the 4q D4Z4 subtelomeric array, in association with DUX4-permissive haplotypes. This main form is indicated as...
Hum. Mutat. - issue: 4 - volume: 36 - pages: 443-453.

Sibertin-Blanc, C.  et al. 2015

Vascular Endothelial Growth Factor A c.*237C > T polymorphism is associated with bevacizumab efficacy and related hypertension in metastatic colorectal cancer

Background: No predictive marker has been yet identified for bevacizumab which is widely used in metastatic colorectal cancer. Aims: Evaluate impact of single nucleotide polymorphisms involved in...
Dig. Liver Dis. - issue: 4 - volume: 47 - pages: 331-337.

Elkhatib, R.  et al. 2015

Nuclear envelope remodelling during human spermiogenesis involves somatic B-type lamins and a spermatid-specific B3 lamin isoform

The nuclear lamina (NL) is a filamentous protein meshwork, composed essentially of lamins, situated between the inner nuclear membrane and the chromatin. There is mounting evidence that the NL plays a...
Mol. Hum. Reprod. - issue: 3 - volume: 21 - pages: 225-236.

Salort-Campana, E.  et al. 2015

Low penetrance in facioscapulohumeral muscular dystrophy type 1 with large pathological D4Z4 alleles: a cross-sectional multicenter study

Background: Facioscapulohumeral muscular dystrophy type 1(FSHD1) is an autosomal dominant disorder associated with the contraction of D4Z4 less than 11 repeat units (RUs) on chromosome 4q35....
Orphanet J. Rare Dis. - issue: - volume: 10 - pages: 2.

Bartoli, M.  et al. 2014

Exome Sequencing as a Second-Tier Diagnostic Approach for Clinically Suspected Dysferlinopathy Patients

Introduction: Autosomal recessive muscular dystrophies are heterogeneous genetic disorders, with 39 genes currently implicated. Genetic diagnosis using targeted single-gene analysis by Sanger...
Muscle Nerve - issue: 6 - volume: 50 - pages: 1007-1010.

Kergourlay, V.  et al. 2014

Identification of Splicing Defects Caused by Mutations in the Dysferlin Gene

Missense, iso-semantic, and intronic mutations are challenging for interpretation, in particular for their impact in mRNA. Various tools such as the Human Splicing Finder (HSF) system could be used to...
Hum. Mutat. - issue: 12 - volume: 35 - pages: 1532-1541.

Xi, J.  et al. 2014

Clinical heterogeneity and a high proportion of novel mutations in a Chinese cohort of patients with dysferlinopathy

Background and Aims: Dysferlinopathies are a group of autosomal recessive muscular dystrophies caused by mutations in the dysferlin gene. This study presents clinical features and the mutational...
Neurol. India - issue: 6 - volume: 62 - pages: 635-639.

Bonello-Palot, N.  et al. 2014

Prelamin A accumulation in endothelial cells induces premature senescence and functional impairment

Background: Defects in lamin A maturation result in premature aging syndromes and severe atherosclerosis as observed in the Hutchinson-Gilford Progeria Syndrome. In age-related atherosclerosis,...
Atherosclerosis - issue: 1 - volume: 237 - pages: 45-52.

Puppo, F.  et al. 2014

Molecular defects in FAT1 are associated to facioscapulohumeral dystrophy (FSHD)


Neuromusc. Disord. - issue: 9-10 - volume: 24 - pages: 797-798.