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Towards a better understanding of symptom variations between forms of myotonic dystrophy

On the Left: an image of nuclei of muscle cells of a patient with myotonic dystrophy type 2. DNA is marked blue, toxic RNA containing CCUG repeats is marked red and rbFOX1 protein is marked green. Co-localization of rbFOX1 and the CCUG RNA leads to a yellow marking (overlap of red and green signals).

At right, a figure representing the competition between MBNL1 and rbFOX1 to link RNA containing CCUG repeats in myotonic dystrophy type 2.

rbFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to myotonic dystrophy type 1/type 2 differences.

Sellier C(1), Cerro-Herreros E(2)(3), Blatter M(4), Freyermuth F(1), Gaucherot A(1), Ruffenach F(1), Sarkar P(5), Puymirat J(6), Udd B(7)(8)(9), Day JW(10), Meola G(11)(12), Bassez G(13), Fujimura H(14), Takahashi MP(15), Schoser B(16), Furling D(13), Artero R(2)(3), Allain FHT(4), Llamusi B(17)(18), Charlet-Berguerand N(19)(20)(21)(22).

Nat Commun May 22, 2018

May 22, 2018

Myotonic dystrophy, a rare genetic disease affecting muscles, is known in two forms, the first with greater symptomatic severity. For each type, a repetition of a microsatellite sequence within a specific gene is involved, creating aggregates of toxic RNA. However, the degree of severity of myotonic dystrophy forms 1 and 2 remained unclear. In a study published on May 22th, 2018 in the journal Nature Communications, Nicolas Charlet-Berguerand's team at IGBMC, in collaboration with international research and medical teams, unveils the molecular mechanisms at the origin of the differences in severity between the various forms of the disease.

Myotonic dystrophy, also known as Steinert's disease, is the most common adult form of muscular dystrophy. Patients suffering from this genetic disease experience progressive skeletal muscle atrophy, heart problems and cognitive problems. There is no cure for this disabling disease. Two forms are known, type 1 myotonic dystrophy (DM1) and type 2 myotonic dystrophy (DM2), the latter being much less severe for reasons so far unexplained.

For both types, the repetition of a microsatellite sequence within a gene is at stake. It is expressed as RNA containing long repeats of the tri-nucleotides CUG (in the case of DM1) or CCUG (DM2). RNA containing the CUG or CCUG repeats accumulate in clusters that bind and sequester a protein called MBNL1. The decrease in available MBNL1 level leads to an alteration of the functioning of muscle and neuronal cells.


In the present study, the team of Dr. Nicolas Charlet-Berguerand investigated the involvement of another protein, rbFOX1, which specifically binds CCUG RNA units (associated with type 2 myotonic dystrophy), but does not recognize CUG RNA units (associated with type 1). In addition, the researchers demonstrated that rbFOX1 was in competition with MBNL1 to bind CCUG RNA. RNA binding by rbFOX1 liberates a fraction of the MBNL1 proteins sequestered by toxic CCUG RNA clusters. The release of MBNL1 thus leads to better muscle cell function, which could ultimately explain the lower severity of type 2 myotonic dystrophy. In addition, it was shown that rbFOX1 is bound but not sequestered by CCUG RNAs, therefore it remains available to fulfil its functions.

This discovery, based on cellular and animal (Drosophila) models, confirms the established concept of MBNL1 sequestration as the main cause of cell dysfunction in myotonic dystrophy, which would pave the way for therapeutic research targeting this mechanism.


This study was funded by the European Research Council (ERC), Inserm, ANR, AFM and LabEx-INRT.

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