On keeping strong muscles: from the genetic causes to potential treatments for inherited neuromuscular disorders.

Muscles in our bodies have the ability to contract in order to produce force and motion. Three different types of muscles compose our muscular system: cardiac muscles, which are unique to the heart, smooth muscles, which form the supporting tissue around blood vessels and internal organs, and skeletal muscles, most of which are attached to bones and are responsible for movements. Of the three types, only the skeletal muscles are under our voluntary control.

Inherited neuromuscular disorders (NMDs) are a broad range of medical conditions that impair the functions of skeletal muscles. They lead to progressive weakness and loss of muscle mass and eventually to chronic disabilities, representing a burden to patients, their families, and a strain to public healthcare systems. Two large groups of disorders can result in skeletal muscle defects: muscular dystrophies, associated with defects of the muscles themselves, and inherited neuropathies, associated with defects in the nerves that control muscles movements. Like for other genetic disorders, a crucial step in the study of inherited NMDs lies on the identification of genetic mutations responsible for the disease. This is not only important for diagnosis, but also for understanding the physiological mechanisms that become defective in patients, and eventually designing therapies for their treatment. By combining multi-omics, clinical data, biological samples and predictive models to computational biology, scientists at the NeMus department have made important contributions including the development of promising new therapeutic approaches.

Next generation sequencing (NGS) technologies have revolutionized the fields of research and diagnostics over the past decade. The possibility to routinely sequence genomes of more and more patients has provided an invaluable opportunity to collect and cross-reference data and ultimately to identify genes responsible for a given genetic disorder. These technologies have been instrumental to scientists within the NeMus department for the discovery of several genes and gene mutations involved in neuromuscular diseases.



However, analysis of the growing amounts of data generated by NGS and their relationship to complex clinical profiles requires a substantial effort in developing appropriate bioinformatics systems and tools. The "bioinformatics and Genetics" team led by Pr Christophe Béroud has developed various reference systems to address all steps of translational research. They include the most efficient pathogenicity prediction systems (UMD-Predictor  and HSF  coupled to the VarAFT  annotation and filtration system to rapidly identify disease-causing mutations) among the many harmless genetic variations normally found in the genomes of different individuals . Thanks to this expertise, they are leading the clinical bioinformatics aspects of the RD-Connect FP7 European Project  and are setting-up the French databases for Copy Number Variations [BAnque Nationale des CNV COnstitutionnels - BANCCO] identified in rare diseases and the French Rare Disease Variant Database (RDVD) collecting all variations identified in NGS experiments [http://rdvd.fr]. In addition, they have established mutation databases  for genes involved in cancers, such as the BRCA1/2 genes responsible for breast/ovarian cancers  and genetic diseases including NMDs, as well as patient registries, which compile genetic and clinical information for a given disease. For example, the team has developed the TREAT-NMD global registries  and a national observatory for patients suffering from Facial Scapulo Humeral Dystrophy (FSHD), a neuromuscular disorder that affects primarily the muscles of the face, shoulders and upper arms. This registry contains today data from over 450 patients, making it the largest FSHD database worldwide.

Understanding the clinical data and the genetics of FSHD has been fundamental in the study of the molecular mechanisms that are defective in this disease, a field that has interested the laboratory of Dr Frédérique Magdinier  for several years.

The vast majority of patients with FSHD (95%) carry a genetic mutation on chromosome 4 (at position 4q35). It is located very close to the chromosome end, or telomere, in what is referred to as the subtelomeric region. This region contains a D4Z4-repeat, a stretch of DNA in which a basic unit called D4Z4 is repeated multiple times in tandem. Healthy individuals typically display 11 to 150 D4Z4 units, while FSHD patients display a contraction of the repeat and carry only 1 to 10 D4Z4 units. But this genetic modification is different from those affecting classical genetic diseases, where a mutation is normally found within a gene and alters the gene product in a manner that compromises its function. Instead, contraction of the D4Z4-repeat locally interferes with chromatin, the structure responsible for DNA packaging and compaction inside the nucleus of a cell. Different levels of chromatin compaction are possible, which impact on local accessibility to the information encoded by the DNA: loosely compacted chromatin is permissive of gene expression, while tightly compacted chromatin is not. In healthy individuals, the D4Z4-repeat is associated with tight chromatin and inactive gene expression, but interestingly, both of these characteristics are lost in FSHD patients.

A few years ago, scientists in the laboratory of Dr Frédérique Magdinier  revealed that this is due to the ability of the short D4Z4-repeats to interact with CTCF, a protein known to regulate chromatin structure. In addition, the group has shown that shortening of the repeat causes its relocalisation to the nuclear periphery, a nuclear subdomain involved in the regulation of chromatin.

From a clinical point of view, the first signs of FSHD usually appear during the second decade of life. To understand how healthy muscles all of a sudden become affected in FSHD patients, Frédérique Magdinier and her colleagues explored the molecular features of presymptomatic muscles during development.

“We found that foetal muscle displayed defects reminiscent of FSHD adult patient cells ”, explains Dr Frédérique Magdinier. “In addition, we also observed a global dysregulation of genes involved in muscle development. These results revealed that even though the symptoms of FSHD only appear as the patients reach adulthood, defects are actually already present during muscle development in foetal life”.

In addition, the team has explored large cohorts of patients with typical signs of FSHD as well as asymptomatic carriers and showed that DNA methylation, one of the main epigenetic change associated with the disease is highly variable among individuals. The team has also identified complex chromosomal rearrangements in a subset of patients highlighting the complexity of the disease locus.

These findings have established the importance of studying epigenetic changes and chromatin conformation during muscle development to understand the mechanisms leading to FSHD. Future research is aimed towards a better understanding on both the differentiation of muscle cells and the molecular mechanisms that link the organization of the 4q35 locus to the disease, through the development of cellular models such as induced Pluripotent Stem cells  (iPS).

Dysferlinopathies are a group of heterogenous neuromuscular disorders that display highly variable symptoms, ranging from mild to severe functional disabilities. They are all linked to mutations in dysferlin (DYSF), a gene that encodes a large protein important upon damage for repairing the membrane that covers the muscle fibres. To date, over 400 different mutations within the DYSF gene are known to cause disease. Scientists from the MMG have a long experience in diagnosing dysferlinopathies, and have largely contributed to identifying these mutations. The laboratory of Dr Marc Bartoli  has recently built a public database that compiles all the mutations found in patients and their relatives, together with the clinical information available for each individual. This database represents a valuable tool for clinicians and scientists for the understanding of this group of disorders.

Beyond their interest in diagnostics, Marc Bartoli and his colleagues have set out to explore therapeutic strategies for the treatment of dysferlinopathies. They have channelled their efforts towards developing a method based on exon-skipping, which takes advantage of the very structure of genes and the way in which they are processed for expression.

To skip or not to skip an exon – how does it work?

Structurally, eukaryotic genes are composed of exons and introns. Exons are the elements that are ultimately expressed and translated into a protein, while introns are non-coding sequences located between exons that are removed before producing the protein. Gene expression starts by transcription, a process in which the information on the DNA is copied into a molecule of another nucleic acid called RNA. Through a mechanism called splicing, the introns are removed from the RNA and the exons are joined together end-to-end. The resulting mature RNA molecule is then translated into the final protein.

Exon-skipping for the treatment of genetic disorders is based on RNA splicing. The idea is to trick the cells into splicing out the exon that carries a genetic mutation such that it is no longer translated. The resulting protein is shorter and may not be fully functional, but in some cases it retains a certain degree of functionality that can at least partially rescue the defects caused by the mutated protein. This method has proven promising for the treatment of another severe genetic disorder characterized by progressive muscle degeneration: Duchenne Muscular Dystrophy (DMD).

So, can exon-skipping be used for the treatment of dysferlinopathies?

Deletion of exon 32 had been found in an individual to cause a very mild version of the disease. The scientists therefore reasoned that a protein lacking the information from exon 32 would be sufficiently active to rescue more severe cases of dysferlinopathies.

“We developed a method for skipping this exon and asked if the resulting protein was able to rescue the defects seen in cells derived from two patients. Surprisingly, we found that although the new protein was expressed at low levels, the cells had become fully capable of repairing lesions in their membrane, indicating that the therapy had worked”, declares Dr Marc Bartoli.

These results established exon-skipping as a promising therapeutic strategy for the treatment of dysferlinopathies. Further pre-clinical studies in mice are currently on the way before translating these results into the development of clinical trials. Finally, similar approaches are also being developed for the treatment of other neuromuscular disorders.

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: .

Beroud, C.  et al. 2016

BRCA Share: A Collection of Clinical BRCA Gene Variants

As next-generation sequencing increases access to human genetic variation, the challenge of determining clinical significance of variants becomes ever more acute. Germline variants in the BRCA1 and...
Hum. Mutat. - issue: 12 - volume: 37 - pages: 1318-1328.

Oetting, WS.  et al. 2016

Clinical Interpretation of Variants from Next-Generation Sequencing: The 2016 Scientific Meeting of the Human Genome Variation Society

Hum. Mutat. - issue: 10 - volume: 37 - pages: 1110-1113.

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

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

Miltgen, M.  et al. 2016

Novel Heterozygous Mutation in ANO3 Responsible for Craniocervical Dystonia

Mov. Disord. - issue: 8 - volume: 31 - pages: 1251-1252.

Chateau, A.  et al. 2016

SIRT1 Deficiency in endothelial progenitor cells drives pro-senescent microparticles release through MKK6 upregulation

J. Thromb. Haemost. - issue: - volume: 14 - pages: 139-139.

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

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

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

Lecocq, C.  et al. 2016

Delayed-onset Friedreich's ataxia revisited

BackgroundFriedreich's ataxia usually occurs before the age of 25. Rare variants have been described, such as late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia, occurring after 25...
Mov. Disord. - issue: 1 - volume: 31 - pages: 62-69.

Arslan-Kirchner, M.  et al. 2016

Clinical utility gene card for: Hereditary thoracic aortic aneurysm and dissection including next-generation sequencing-based approaches

Eur. J. Hum. Genet. - issue: 1 - volume: 24 - pages: 146-150.

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.

Robin, JD.  et al. 2015

SORBS2 transcription is activated by telomere position effect-over long distance upon telomere shortening in muscle cells from patients with facioscapulohumeral dystrophy

DNA is organized into complex three-dimensional chromatin structures, but how this spatial organization regulates gene expression remains a central question. These DNA/chromatin looping structures can...
Genome Res. - issue: 12 - volume: 25 - pages: 1781-1790.

Pilliod, J.  et al. 2015

New Practical Definitions for the Diagnosis of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

Objective: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by mutations in the SACS gene. SACS encodes sacsin, a protein whose function remains unknown, despite the...
Ann. Neurol. - issue: 6 - volume: 78 - pages: 871-886.

Boushaki, S.  et al. 2015

Prevalence of BTK mutations in male Algerian patterns with agammaglobulinemia and severe B cell lymphopenia

X linked agammaglobulinemia (XLA) is the first described primary immunodeficiency and the most common form of agammaglobulinemia. It is characterized by susceptibility to recurrent infections,...
Clin. Immunol. - issue: 2 - volume: 161 - pages: 286-290.

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.

Mariot, V.  et al. 2015

Correlation between low FAT1 expression and early affected muscle in FSHD

Neuromusc. Disord. - issue: - volume: 25 - pages: S312-S312.

Bannwarth, S.  et al. 2015

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

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

Rapetti-Mauss, R.  et al. 2015

A mutation in the Gardos channel is associated with hereditary xerocytosis

The Gardos channel is a Ca2+-sensitive, intermediate conductance, potassium selective channel expressed in several tissues including erythrocytes and pancreas. In normal erythrocytes, it is involved...
Blood - issue: 11 - volume: 126 - pages: 1273-1280.

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

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

Barckmann, B.  et al. 2015

Aubergine iCLIP Reveals piRNA-Dependent Decay of mRNAs Involved in Germ Cell Development in the Early Embryo

The Piwi-interacting RNA (piRNA) pathway plays an essential role in the repression of transposons in the germline. Other functions of piRNAs such as post-transcriptional regulation of mRNAs are now...
Cell Reports - issue: 7 - volume: 12 - pages: 1205-1216.

Bannwarth, S.  et al. 2015

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

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

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.

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.

Nguyen, K.  et al. 2015

Incidental findings on array comparative genomic hybridization: detection of carrier females of dystrophinopathy without any family history

Array comparative genomic hybridization (aCGH) has progressively replaced conventional karyotype in the diagnostic strategy of intellectual disability (ID) and congenital malformations. This technique...
Clin. Genet. - issue: 5 - volume: 87 - pages: 488-491.

Joly, D.  et al. 2015

Rare inherited disorders with renal involvement-approach to the patient

The list of rare inherited disorders with renal involvement is rapidly growing. Many are single gene diseases affecting children, but cases are not restricted to pediatrics and diagnosis is often...
Kidney Int. - issue: 5 - volume: 87 - pages: 901-908.

Portilho, DM.  et al. 2015

miRNA Expression in Control and FSHD Fetal Human Muscle Biopsies

Background Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disorder and is one of the most common forms of muscular dystrophy. We have recently shown that some hallmarks of FSHD...
PLoS One - issue: 2 - volume: 10 - pages: e0116853.

Manes, G.  et al. 2015

High Prevalence of PRPH2 in Autosomal Dominant Retinitis Pigmentosa in France and Characterization of Biochemical and Clinical Features

PURPOSE: To assess the prevalence of PRPH2 in autosomal dominant retinitis pigmentosa (adRP), to report 6 novel mutations, to characterize the biochemical features of a recurrent novel mutation, and...
Am. J. Ophthalmol. - issue: 2 - volume: 159 - pages: 302-314.

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.

Badja, C.  et al. 2014

Efficient and Cost-Effective Generation of Mature Neurons From Human Induced Pluripotent Stem Cells

For years, our ability to study pathological changes in neurological diseases has been hampered by the lack of relevant models until the recent groundbreaking work from Yamanaka's group showing that...
Stem Cells Transl. Med. - issue: 12 - volume: 3 - pages: 1467-1472.

Bannwarth, S.  et al. 2014

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

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

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

Bannwarth, S.  et al. 2014

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

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.

Robin, JD.  et al. 2014

Telomere position effect: regulation of gene expression with progressive telomere shortening over long distances

While global chromatin conformation studies are emerging, very little is known about the chromatin conformation of human telomeres. Most studies have focused on the role of telomeres as a tumor...
Genes Dev. - issue: 22 - volume: 28 - pages: 2464-2476.

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.

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.

Mazuc, E.  et al. 2014

In-Cell Intrabody Selection from a Diverse Human Library Identifies C12orf4 Protein as a New Player in Rodent Mast Cell Degranulation

The high specificity of antibodies for their antigen allows a fine discrimination of target conformations and post-translational modifications, making antibodies the first choice tool to interrogate...
PLoS One - issue: 8 - volume: 9 - pages: e104998.

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.

Thompson, R.  et al. 2014

RD-Connect: An Integrated Platform Connecting Databases, Registries, Biobanks and Clinical Bioinformatics for Rare Disease Research

Research into rare diseases is typically fragmented by data type and disease. Individual efforts often have poor interoperability and do not systematically connect data across clinical phenotype,...
J. Gen. Intern. Med. - issue: - volume: 29 - pages: S780-S787.

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.

Etienne-Grimaldi, M.  et al. 2014

Molecular patterns in deficient mismatch repair colorectal tumours: results from a French prospective multicentric biological and genetic study

Background: To test the prognostic value of tumour protein and genetic markers in colorectal cancer (CRC) and examine whether deficient mismatch repair (dMMR) tumours had a distinct profile relative...
Br. J. Cancer - issue: 11 - volume: 110 - pages: 2728-2737.

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.

Boennemann, CG.  et al. 2014

Diagnostic approach to the congenital muscular dystrophies

Congenital muscular dystrophies (CMDs) are early onset disorders of muscle with histological features suggesting a dystrophic process. The congenital muscular dystrophies as a group encompass great...
Neuromusc. Disord. - issue: 4 - volume: 24 - pages: 289-311.

Vassallo, PF.  et al. 2014

Accelerated senescence of cord blood endothelial progenitor cells in premature neonates is driven by SIRT1 decreased expression

Epidemiological and experimental studies indicate that early vascular dysfunction occurs in low-birth-weight subjects, especially preterm (PT) infants. We recently reported impaired angiogenic...
Blood - issue: 13 - volume: 123 - pages: 2116-2126.

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.

Robellet, X.  et al. 2014

A Genetic Screen for Functional Partners of Condensin in Fission Yeast

Mitotic chromosome condensation is a prerequisite for the accurate segregation of chromosomes during cell division, and the conserved condensin complex a central player of this process. However, how...
G3-Genes Genomes Genet. - issue: 2 - volume: 4 - pages: 373-381.

Bladen, CL.  et al. 2014

Mapping the differences in care for 5,000 Spinal Muscular Atrophy patients, a survey of 24 national registries in North America, Australasia and Europe

Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder characterised by the degeneration of motor neurons and progressive muscle weakness. It is caused by homozygous deletions in the...
J. Neurol. - issue: 1 - volume: 261 - pages: 152-163.

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.

Callier, P.  et al. 2013

Systematic molecular and cytogenetic screening of 100 patients with marfanoid syndromes and intellectual disability

The association of marfanoid habitus (MH) and intellectual disability (ID) has been reported in the literature, with overlapping presentations and genetic heterogeneity. A hundred patients (71 males...
Clin. Genet. - issue: 6 - volume: 84 - pages: 507-521.

Poulain, S.  et al. 2013

Genome wide SNP array identified multiple mechanisms of genetic changes in Waldenstrom macroglobulinemia

SNP array (SNPa) was developed to detect copy number alteration (CNA) and loss of heterozygosity (LOH) without copy number changes, CN-LOH. We aimed to identify novel genomic aberrations using SNPa in...
Am. J. Hematol. - issue: 11 - volume: 88 - pages: 948-954.

Bladen, CL.  et al. 2013

The TREAT-NMD Duchenne Muscular Dystrophy Registries: Conception, Design, and Utilization by Industry and Academia

Duchenne muscular dystrophy (DMD) is an X-linked genetic disease, caused by the absence of the dystrophin protein. Although many novel therapies are under development for DMD, there is currently no...
Hum. Mutat. - issue: 11 - volume: 34 - pages: 1449-1457.

Robin, JD.  et al. 2013

Length dependent telomere looping affects long-distant gene expression (5 Mb) in FSHD

Neuromusc. Disord. - issue: 9-10 - volume: 23 - pages: 824-824.

Ferreboeuf, M.  et al. 2013

DUX 4 and DUX4 downstream target genes are expressed in fetal FSHD muscles

Neuromusc. Disord. - issue: 9-10 - volume: 23 - pages: 823-823.

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.

Humbertclaude, V.  et al. 2013

Phenotypic heterogeneity and phenotype-genotype correlations in dystrophinopathies: Contribution of genetic and clinical databases

The objective of this work was to study the natural history of dystrophinopathies and the genotype-phenotype correlations made possible by the development of the clinical part of the French DMD...
Rev. Neurol. - issue: 8-9 - volume: 169 - pages: 583-594.

Boussouar, A.  et al. 2013

Acacetin and Chrysin, Two Polyphenolic Compounds, Alleviate Telomeric Position Effect in Human Cells

We took advantage of the ability of human telomeres to silence neighboring genes (telomere position effect or TPE) to design a high-throughput screening assay for drugs altering telomeres. We...
Mol. Ther.-Nucl. Acids - issue: - volume: 2 - pages: e116.

McDonnell, CM.  et al. 2013

Ecto- and endoparasite induce similar chemical and brain neurogenomic responses in the honey bee (Apis mellifera)

Background: Exclusion from a social group is an effective way to avoid parasite transmission. This type of social removal has also been proposed as a form of collective defense, or social immunity, in...
BMC Ecol. - issue: - volume: 13 - pages: 25.

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.

Diala, I.  et al. 2013

Telomere protection and TRF2 expression are enhanced by the canonical Wnt signalling pathway

The DNA-binding protein TRF2 is essential for telomere protection and chromosome stability in mammals. We show here that TRF2 expression is activated by the Wnt/beta-catenin signalling pathway in...
EMBO Rep. - issue: 4 - volume: 14 - pages: 356-363.

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.

Roche, S.  et al. 2013

Comparative analysis of protein expression of three stem cell populations: Models of cytokine delivery system in vivo

Several mechanisms mediate the regenerative and reparative capacity of stem cells, including cytokine secretion; therefore these cells can act as delivery systems of therapeutic molecules. Here we...
Int. J. Pharm. - issue: 1 - volume: 440 - pages: 72-82.

De Paula, AM.  et al. 2012

Further Heterogeneity in Myopathy with Tubular Aggregates?

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.

Herbaux, C.  et al. 2012

B-Cell-Specific Transcription Factor BACH2 Involved in the Clinical Behavior Heterogeneity of Waldenstrom Macroglobulinemia

Blood - issue: 21 - volume: 120 - pages: .

Carmignac, V.  et al. 2012

In-Frame Mutations in Exon 1 of SKI Cause Dominant Shprintzen-Goldberg Syndrome

Shprintzen-Goldberg syndrome (SGS) is characterized by severe marfanoid habitus, intellectual disability, camptodactyly, typical facial dysmorphism, and craniosynostosis. Using family-based exome...
Am. J. Hum. Genet. - issue: 5 - volume: 91 - pages: 950-957.

Fahiminiya, S.  et al. 2012

Improvement of 2D-PAGE Resolution of Human, Porcine and Canine Follicular Fluid: Comparison of Two Immunodepletion Columns

Contents Follicular fluid provides the microenvironment within which somatic cells proliferate and differentiate, and the oocyte matures. It contains a number of soluble factors implicated in various...
Reprod. Domest. Anim. - issue: 5 - volume: 47 - pages: e67-e70.

Salgado, D.  et al. 2012

MyMiner: a web application for computer-assisted biocuration and text annotation

Motivation: The exponential growth of scientific literature has resulted in a massive amount of unstructured natural language data that cannot be directly handled by means of bioinformatics tools....
Bioinformatics - issue: 17 - volume: 28 - pages: 2285-2287.

Boehm, J.  et al. 2012

Mutation Spectrum in the Large GTPase Dynamin 2, and Genotype-Phenotype Correlation in Autosomal Dominant Centronuclear Myopathy

Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei....
Hum. Mutat. - issue: 6 - volume: 33 - pages: 949-959.

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.

Galati, A.  et al. 2012

TRF2 Controls Telomeric Nucleosome Organization in a Cell Cycle Phase-Dependent Manner

Mammalian telomeres stabilize chromosome ends as a result of their assembly into a peculiar form of chromatin comprising a complex of non-histone proteins named shelterin. TRF2, one of the shelterin...
PLoS One - issue: 4 - volume: 7 - pages: e34386.

Jabbour, R.  et al. 2012

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

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.

Humbertclaude, V.  et al. 2012

Motor and respiratory heterogeneity in Duchenne patients: Implication for clinical trials

Aims: Our objective was to clarify the clinical heterogeneity in Duchenne muscular dystrophy (DMD). Methods: The French dystrophinopathy database provided clinical, histochemical and molecular data of...
Eur. J. Paediatr. Neurol. - issue: 2 - volume: 16 - pages: 149-160.

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.

Bonnans, C.  et al. 2012

Essential requirement for beta-arrestin2 in mouse intestinal tumors with elevated Wnt signaling

beta-Arrestins (Arrb) participate in the regulation of multiple signaling pathways, including Wnt/beta-catenin, the major actor in human colorectal cancer initiation. To better understand the roles of...
Proc. Natl. Acad. Sci. U. S. A. - issue: 8 - volume: 109 - pages: 3047-3052.

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.

Samadi, A.  et al. 2012

Surgical management of patients with Marfan syndrome: Evolution throughout the years

Aim. To evaluate the evolution of surgical management in a large population of patients with Marfan syndrome. Methods. This is a retrospective study of patients fulfilling the Ghent criteria for...
Arch. Cardiovasc. Dis. - issue: 2 - volume: 105 - pages: 84-90.

Jondeau, G.  et al. 2012

Aortic Event Rate in the Marfan Population A Cohort Study

Background-Optimal management, including timing of surgery, remains debated in Marfan syndrome because of a lack of data on aortic risk associated with this disease. Methods and Results-We used our...
Circulation - issue: 2 - volume: 125 - pages: 226-232.