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ANR funded project

Blanc - SVSE 1 - Physiologie, physiopathologie, santé publique (Blanc SVSE 1) 2013
Projet FSHDecipher

Molecular mechanisms of Facio-Scapulo-Humeral Dystrophy: from the contribution of genomics to the mecanisitic exploration of new regulatory pathways for the 4q35 locus.

Facio-Scapulo-Humeral Dystrophy (FSHD), the first most common myopathy in adult is transmitted, in the majority of cases, with an autosomal dominant mode of inheritance. Its typical clinical phenotype is characterized by the progressive involvement of facial, scapulohumeral and anterior forelegs muscles, which is frequently asymmetric and can spread to pelvic and abdominal muscles in most severe cases. The majority of patients with typical FSHD phenotype (95%) carry a contraction of an array of repeated sequences, called D4Z4 located in the telomeric region of chromosome 4 (4q35 locus) and a “permissive” chromosome 4 (FSHD1). The current model explaining FSHD1 is based on the following postulates: a reduction in the number of D4Z4 macrosatellite in the subtelomeric 4q35 region, in the context of a permissive allele (presence of a 4q region containing a pLAM polyadenylation site distal to the last D4Z4 repeat), the presence of a permissive SSLP proximal to the first repeat and hypomethylation of the shortened D4Z4 array is associated with ectopic expression of a long form of the DUX4 transcript (DUX4fl) produced from the last D4Z4 repeat. This long DUX4 transcript might lead to the production of a transcription factor able to activate a number of other genes. In at least 5-10% of patients with a typical FSHD phenotype, the length of the D4Z4 array is identical to unaffected individuals suggesting alternative pathway(s) to the pathology. Most of these patients display a profound hypomethylation of both chromosomes 4 and 10 in association to a permissive chromosome 4 and expression of the DUX4fl pathogenic transcript. Recent investigations on a number of FSHD2 individuals and families unraveled the presence of mutation in the gene encoding the SMCHD1 protein, contributing to chromatin regulation in this subset of patients. However, on the genetic and mechanistic point of view, other findings require further investigation to fully understand the disease onset, progression and penetrance.
Although one cannot exclude that the current model explains FSHD pathogenesis in many cases, a number of observation do not fit into the current model and FSHD pathogenesis appears more complex. Therefore, although DUX4-fl expression represents an interesting indicator, the direct involvement of this gene in the pathology remains puzzling. In addition, preliminary results obtained by all 4 partners suggest the dysregulation of other pathways including other genes in the 4q35 region, novel non-coding RNA or miRNAs either in FSHD1 or in FSHD2. We will explore these new pathways in order to define their relevance in FSHD pathogenesis. Furthermore, our goal here is to develop new methods for the characterization of atypical cases of FSHD and to determine how epigenetic changes contribute to the regulation of the 4q35 region and the pathology. We will investigate more deeply the mechanism leading to this asymmetrical, variable and selective muscular dystrophy by creating new cellular models based on the facilities and protocols available at the different partners’ institute (primary myoblasts and myotubes, immortalized myoblasts, induced pluripotent cells).
The novelty and originality of the project resides in the fact that a broad spectrum of aspects (epigenetics, genetics, regulatory factors, biomarkers) will be investigated based on the exploration of a unique cohort of patients including typical and atypical cases.
With regard to feasibility, the design of the project minimizes the kind of risk inherent to an approach focused on only one aspect. Encouraging preliminary results that form the project’s ‘baseline’ substantially increases our probability of success.


AMU Aix Marseille Université

CHU de NICE Centre Hospitalier Universitaire de NICE

INSERM-AMU Génétique Médicale et Génomique Fonctionnelle, INSERM UMR S_910

INSERM-CNRS-Institut de Myologie-Paris VI Thérapies des maladies du muscle strié

ANR grant: 439 998 euros
Beginning and duration: novembre 2013 - 42 mois


ANR Programme: Blanc - SVSE 1 - Physiologie, physiopathologie, santé publique (Blanc SVSE 1) 2013

Project ID: ANR-13-BSV1-0004

Project coordinator:
Madame Frédérique Magdinier (Aix Marseille Université)


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The project coordinator is the author of this abstract and is therefore responsible for the content of the summary. The ANR disclaims all responsibility in connection with its content.