Muscular dystrophies, myopathies, inherited peripheral neuropathies and hereditary ataxias groups of diseases studied by the team are part of the large family of neuromuscular disorders (NMD), a set of hereditary diseases ultimately leading to muscle dysfunction, due to muscle or nerve abnormalities. Although quite different in terms of affected genes and pathways, these diseases are defined by a strong genetic heterogeneity leading to complex physiopathological pathways. Improving diagnosis of these diseases, the understanding of the pathomechanisms and defining new treatments are primary goals that we want to achieve.



Group leader: Martin Krahn

The research group “Translational Genomics” will constitute the genomics resource of the team, and coordinate translational research projects focused on the applicative development of novel genome analysis technologies, with the aim of improving genetic diagnosis in clinical applications, and novel gene identification. Efforts will be made specifically to further increase diagnostic yields and validate the implication of novel genes in neuromuscular diseases through (i) the adaption of Whole-exome and Whole-genome Next Generation Sequencing (NGS), and (ii) the development of functional tests for the characterization of the pathogenic impact of sequence variants, the latter points will be enriched and positioned in a highly propitious research environment through the close collaborations with the group lead by Pr. C. Béroud (Bioinformatics and genetics), the group led by Dr. F. Magdinier (Epigenetics, Chromatin & Disease modeling), and the newly created genomics platform of our Research Unit headed by Dr. V. Delague.

The “Translational Genomics” relays on our expertise acquired in this field during the past 8 years, in particular through our participation to four FP7 European Projects (NMD-CHIP, BIO-NMD, LEB’IN and NEUROMICS), the MYOCAPTURE project, and longstanding collaboration-networks in the Mediterranean area (A*MIDEX RARE-MED project) Moreover, this group is closely linked to the diagnostic activities and the constitution of large national and international cohorts within the Department of Medical Genetics of Marseille (Hôpital d’Enfants de La Timone; Assistance Publique - Hôpitaux de Marseille), in strong relationship with the Reference Center for Neuromuscular Diseases and Lateral Amyotrophic Sclerosis in Marseille (Pr. J. Pouget and Pr. S. Attarian). Noteworthy, for different types of neuromuscular diseases on which our “NMD Department” focuses (i.e. Dysferlinopathies, Calpainopathies, GNEpathies, FSHD, different forms of CMT-neuropathies), the Department of Medical Genetics of Marseille is the national French reference laboratory for genetic diagnosis, receiving the large majority of patient samples throughout France.

 

Group leader: Valérie Delague

Using innovative approaches, we will identify new defective genes/proteins in NMD diseases. This group “Physiopathology of neuromuscular disorders” will focus on the comprehension of the pathomechanisms underlying the diseases caused by these new mutations/disease genes. The objectives here are to pave the way for the development of new therapies, by i) studying the physiopathological mechanisms underlying the studied diseases, due to mutations in new defective genes in NMD, or new mutations in genes already involved in other hereditary diseases (NMD or not); and ii) determining the interactions between these proteins in normal and pathological conditions. Identifying new players in NMD diseases is of major importance, not only for molecular diagnosis and genetic counselling of families affected with these diseases, but also toward understanding the role of normal and mutant proteins in muscle and peripheral nerve. These genes can be viewed as the result of a functional screen revealing crucial players in the biology of muscles or nerves, the interaction between nerves and muscle or between Schwann cell and neurons.

 

Group leader: Marc Bartoli

For years, neuromuscular disorders have been considered as incurable diseases, however for fifteen years several proof of concept (PoC) have emerged and rise new hope for patients. The research group “Biotherapies targeted to neuromuscular disorders “, directed by Marc Bartoli aims to develop innovative therapeutic approaches for different neuromuscular diseases. The “Biotherapies targeted to neuromuscular disorders” group rely on a strong expertise obtained during the past years, in particular M. Bartoli contributed in the establishment of seven PoC that demonstrate the feasibility of several approaches for three distinct neuromuscular diseases and participated in clinical trials. This group will be closely linked to activities of the two other groups constituting the NeuroMyology team in particular by valorizing studies of patients presenting with extreme phenotype.

In particular, we develop novel therapeutic approaches, based on particular clinical observations and mutational data from our large cohort of patients. We will pursue our previous work towards further preclinical testing of therapeutic strategies developed by our group in particular: transcript rescue strategies (Exon skipping/Trans-splicing…).   

Besides these transcript rescue strategies, we will also develop gene transfer strategy. We also advance “classical” pharmaceutical therapeutic approaches to neuromuscular diseases, under the condition that pharmaceutical targets are identified based on the molecular pathophysiology.
Finally, we intend to define the best strategy using preclinical models to assay efficacy of considered approaches to alleviate neuromuscular diseases. Ultimately, if some approaches are successful, they may lead towards translational strategies and we will further establish partnerships at national and international level, to accelerate implementation of innovation. We will make sure that the process of design, development and validation of our therapeutic strategies will go through a process of clinical trial evaluation. This part of the project represents a strategic decision for the team with the objective of introducing the knowledge and collaborations for the translation of our pre-clinical research projects into the development of clinical trials. In this context, we envisaged to participate in clinical trials promoted by biotech/pharmacological companies before launching our own clinical trials.

 

Cerino, M.  et al. 2017

Genetic characterization of a French cohort of GNE-mutation negative inclusion body myopathy patients using 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: - volume: - pages: .

El Bazzal, L.  et al. 2016

New Missense Mutations in the Vaccinia-Related Kinase 1 Gene Are Associated with Autosomal Recessive Axonal Charcot-Marie-Tooth Disease

WOS:000383856200260
J. Peripher. Nerv. Syst. - issue: 3 - volume: 21 - pages: 251-252.

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.

Lacoste, C.  et al. 2016

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

WOS:000372660600027
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.

Yoon, G.  et al. 2016

Reply: Autosomal recessive cerebellar ataxia caused by a homozygous mutation in PMPCA

WOS:000371694600006
Brain - issue: - volume: 139 - pages: e20.

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.

Leikina, E.  et al. 2015

Annexin A1 Deficiency does not Affect Myofiber Repair but Delays Regeneration of Injured Muscles

Repair and regeneration of the injured skeletal myofiber involves fusion of intracellular vesicles with sarcolemma and fusion of the muscle progenitor cells respectively. In vitro experiments have...
Sci Rep - issue: - volume: 5 - pages: 18246.

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.

Gorokhova, S.  et al. 2015

Comparing targeted exome and whole exome approaches for genetic diagnosis of neuromuscular disorders

Massively parallel sequencing is rapidly becoming a widely used method in genetic diagnostics. However, there is still no clear consensus as to which approach can most efficiently identify the...
Appl. Transl. Genomics - issue: - volume: 7 - pages: 26-31.

Capo-Chichi, J.  et al. 2015

Neuroblastoma Amplified Sequence (NBAS) mutation in recurrent acute liver failure: Confirmatory report in a sibship with very early onset, osteoporosis and developmental delay

Background: Recently, biallelic mutations in the Neuroblastoma Amplified Sequence NBAS gene have been identified in ten patients that present recurrent acute liver failure (RALF) in early infancy. In...
Eur. J. Med. Genet. - issue: 12 - volume: 58 - pages: 637-641.

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.

Bannwarth, S.  et al. 2015

Reply: Is CHCHD10 Pro34Ser pathogenic for frontotemporal dementia and amyotrophic lateral sclerosis?

WOS:000365136200006
Brain - issue: - volume: 138 - pages: E386-U20.

Barthélémy, F.  et al. 2015

Exon 32 Skipping of Dysferlin Rescues Membrane Repair in Patients' Cells

Dysferlinopathies are a family of disabling muscular dystrophies with LGMD2B and Miyoshi myopathy as the main phenotypes. They are associated with molecular defects in DYSF, which encodes dysferlin, a...
J Neuromuscul Dis - issue: 3 - volume: 2 - pages: 281-290.

Bannwarth, S.  et al. 2015

Reply: A distinct clinical phenotype in a German kindred with motor neuron disease carrying a CHCHD10 mutation

WOS:000361396200003
Brain - issue: - volume: 138 - pages: e377.

Bannwarth, S.  et al. 2015

Reply: CHCHD10 mutations in Italian patients with sporadic amyotrophic lateral sclerosis

WOS:000360578700006
Brain - issue: - volume: 138 - pages: E373-U13.

Kergourlay, V.  et al. 2015

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

WOS:000367235500009
Ann. Clin. Transl. Neurol. - issue: 7 - volume: 2 - pages: 783-784.

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.

Cerino, M.  et al. 2015

Novel Pathogenic Variants in a French Cohort Widen the Mutational Spectrum of GNE Myopathy

BACKGROUND: GNE myopathy is a rare autosomal recessively inherited muscle disease resulting from mutations in the gene encoding GNE (UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase), a...
J Neuromuscul Dis - issue: 2 - volume: 2 - pages: 131-136.

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.

Bannwarth, S.  et al. 2014

Reply: Two novel mutations in conserved codons indicate that CHCHD10 is a gene associated with motor neuron disease

WOS:000346761200002
Brain - issue: - volume: 137 - pages: e310.

Bannwarth, S.  et al. 2014

Reply: Mutations in the CHCHD10 gene are a common cause of familial amyotrophic lateral sclerosis

WOS:000346761200004
Brain - issue: - volume: 137 - pages: e312.

Bannwarth, S.  et al. 2014

Reply: Are CHCHD10 mutations indeed associated with familial amyotrophic lateral sclerosis?

WOS:000346761200006
Brain - issue: - volume: 137 - pages: e314.

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.

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.

Puppo, F.  et al. 2014

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

WOS:000342870200023
Neuromusc. Disord. - issue: 9-10 - volume: 24 - pages: 797-798.

Desgeorges, MM.  et al. 2014

Post-transcriptional regulation of autophagy in C2C12 myotubes following starvation and nutrient restoration

In skeletal muscle, autophagy is activated in multiple physiological and pathological conditions, notably through the transcriptional regulation of autophagy-related genes by FoxO3. However, recent...
Int. J. Biochem. Cell Biol. - issue: - volume: 54 - pages: 208-216.

Jaka, O.  et al. 2014

Entire CAPN3 gene deletion in a patient with limb-girdle muscular dystrophy type 2A

Limb-girdle muscular dystrophy type 2A (LGMD2A) due to mutations in the CAPN3 gene is one of the most common of autosomal recessive limb-girdle muscular dystrophies. We describe a patient who had a...
Muscle Nerve - issue: 3 - volume: 50 - pages: 448-453.

Bannwarth, S.  et al. 2014

A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement

Using whole-exome sequencing, Bannwarth et al. identify a missense mutation in the mitochondrial gene, CHCHD10, in two families with frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS)....
Brain - issue: - volume: 137 - pages: 2329-2345.

Defour, A.  et al. 2014

Dysferlin regulates cell membrane repair by facilitating injury-triggered acid sphingomyelinase secretion

Dysferlin deficiency compromises the repair of injured muscle, but the underlying cellular mechanism remains elusive. To study this phenomenon, we have developed mouse and human myoblast models for...
Cell Death Dis. - issue: - volume: 5 - pages: e1306.

Mehawej, C.  et al. 2014

The Impairment of MAGMAS Function in Human Is Responsible for a Severe Skeletal Dysplasia

Impairment of the tightly regulated ossification process leads to a wide range of skeletal dysplasias and deciphering their molecular bases has contributed to the understanding of this complex...
PLoS Genet. - issue: 5 - volume: 10 - pages: e1004311.

Defour, A.  et al. 2014

Imaging Cell Membrane Injury and Subcellular Processes Involved in Repair

The ability of injured cells to heal is a fundamental cellular process, but cellular and molecular mechanisms involved in healing injured cells are poorly understood. Here assays are described to...
J. Vis. Exp. - issue: 85 - volume: - pages: e51106.

Blandin, G.  et al. 2013

A human skeletal muscle interactome centered on proteins involved in muscular dystrophies: LGMD interactome

Background: The complexity of the skeletal muscle and the identification of numerous human disease-causing mutations in its constitutive proteins make it an interesting tissue for proteomic studies...
Skeletal Muscle - issue: - volume: 3 - pages: 3.

Salort-Campana, E.  et al. 2013

Clinical and molecular diagnosis of facioscapulohumeral dystrophy type 1 (FSHD1) in 2012

Introduction. - Diagnosis of facioscapulohumeral dystrophy type 1 (FSHD1) is supported by a suggestive clinical presentation and associated with a heterozygous contraction of the D4Z4 repeat array on...
Rev. Neurol. - issue: 8-9 - volume: 169 - pages: 573-582.

Boubaker, C.  et al. 2013

A Novel Mutation in FGD4/FRABIN Causes Charcot Marie Tooth Disease Type

Charcot-Marie-Tooth (CMT) disease constitutes a clinically and genetically heterogeneous group of hereditary neuropathies characterized by progressive muscular and sensory loss in the distal...
Ann. Hum. Genet. - issue: - volume: 77 - pages: 336-343.

Linssen, WHJP.  et al. 2013

Long-term follow-up study on patients with Miyoshi phenotype of distal muscular dystrophy

Background and purpose To describe the long-term follow-up of a cohort of 22 patients with the Miyoshi phenotype of distal muscular dystrophy (MMD). Methods A long-term clinical follow-up study was...
Eur. J. Neurol. - issue: 6 - volume: 20 - pages: 968-974.

Boehm, J.  et al. 2013

Constitutive Activation of the Calcium Sensor STIM1 Causes Tubular-Aggregate Myopathy

Tubular aggregates are regular arrays of membrane tubules accumulating in muscle with age. They are found as secondary features in several muscle disorders, including alcohol- and drug-induced...
Am. J. Hum. Genet. - issue: 2 - volume: 92 - pages: 271-278.

De Paula, AM.  et al. 2012

Further Heterogeneity in Myopathy with Tubular Aggregates?

WOS:000311615100035
Muscle Nerve - issue: 6 - volume: 46 - pages: 984-985.

Attarian, S.  et al. 2012

Recommendations for the management of facioscapulohumeral muscular dystrophy in 2011

Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disease, characterized by an autosomal dominant mode of inheritance, facial involvement, and selectivity and asymmetry of muscle...
Rev. Neurol. - issue: 12 - volume: 168 - pages: 910-918.

Kannan, MA.  et al. 2012

Distal myopathy with rimmed vacuoles and inflammation: a genetically proven case

Distal myopathy with rimmed vacuoles (DMRV) is a major entity of distal myopathy. It is an autosomal recessive disorder and is due to mutations in the GNE gene that regulates the synthesis of sialic...
Neurol India - issue: 6 - volume: 60 - pages: 631-634.

Baudot, C.  et al. 2012

Two novel missense mutations in FGD4/FRABIN cause Charcot-Marie-Tooth type 4H (CMT4H)

By sequencing of the FGD4 coding sequence in a cohort of 101 patients affected by autosomal recessive demyelinating Charcot-Marie-Tooth disease (CMT), we have identified two novel missense mutations...
J. Peripher. Nerv. Syst. - issue: 2 - volume: 17 - pages: 141-146.

Lostal, W.  et al. 2012

Lack of Correlation between Outcomes of Membrane Repair Assay and Correction of Dystrophic Changes in Experimental Therapeutic Strategy in Dysferlinopathy

Mutations in the dysferlin gene are the cause of Limb-girdle Muscular Dystrophy type 2B and Miyoshi Myopathy. The dysferlin protein has been implicated in sarcolemmal resealing, leading to the idea...
PLoS One - issue: 5 - volume: 7 - pages: e38036.

Marion, V.  et al. 2012

Exome sequencing identifies mutations in LZTFL1, a BBSome and smoothened trafficking regulator, in a family with Bardet-Biedl syndrome with situs inversus and insertional polydactyly

Background Bardet-Biedl Syndrome (BBS) is an emblematic recessive genetically highly heterogeneous ciliopathy characterised mainly by polydactyly, retinitis pigmentosa, obesity, cognitive impairment,...
J. Med. Genet. - issue: 5 - volume: 49 - pages: 317-321.

Jabbour, R.  et al. 2012

Epidemiology of Charcot-Marie-Tooth in Lebanon: Clinical, Genetic and Electrophysiological Correlation

WOS:000303204802561
Neurology - issue: - volume: 78 - pages: .

Corbani, S.  et al. 2012

Molecular screening of MECP2 gene in a cohort of Lebanese patients suspected with Rett syndrome: report on a mild case with a novel indel mutation

Background Rett syndrome (RTT), an X-linked, dominant, neurodevelopment disorder represents 10% of female subjects with profound intellectual disability. Mutations in the MECP2 gene are responsible...
J. Intell. Disabil. Res. - issue: 4 - volume: 56 - pages: 415-420.

Poitelon, Y.  et al. 2012

Behavioral and Molecular Exploration of the AR-CMT2A Mouse Model Lmna (R298C/R298C)

In 2002, we identified LMNA as the first gene responsible for an autosomal recessive axonal form of Charcot-Marie-Tooth disease, AR-CMT2A. All patients were found to be homozygous for the same...
Neuromol. Med. - issue: 1 - volume: 14 - pages: 40-52.

Soheili, T.  et al. 2012

Rescue of Sarcoglycan Mutations by Inhibition of Endoplasmic Reticulum Quality Control is Associated with Minimal Structural Modifications

Sarcoglycanopathies (SGP) are a group of autosomal recessive muscle disorders caused by primary mutations in one of the four sarcoglycan genes. The sarcoglycans (alpha-, beta-, gamma-, and...
Hum. Mutat. - issue: 2 - volume: 33 - pages: 429-439.