Dysferlinopathy is the name given to a group of muscle diseases that are caused by mutations in DYSF gene. Dysferlinopathy has two major phenotypes,  “Miyoshi muscular dystrophy 1 (MMD1)” and “Limb-girdle muscular dystrophy autosomal recessive 2 (LGMDR2)”. In these two phenotypes, even though the causal gene is the same, the initial symptoms and the progress of the disease are different. In MMD1, the muscles farther from the torso (hands and feet) are affected first, in contrast, in LGMDR2, the proximal muscles, the muscles close to the torso are affected first. Understanding the mechanisms that underlie the differences in phenotypes will be helpful in diagnostics of the disease, foreseeing the progress, improving the existing treatments and discovering new ones. For this purpose, we - Ozan Ozisik, Mathieu Cerino, Marc Bartoli and Anaïs Baudot - aimed to identify the genes and mutations that can lead to one phenotype or the other in dysferlinopathy using both the genetic data of the dysferlinopathy patients and the curated knowledge on other muscle diseases.

Encadré par Jérôme D. Robin

Telomeres are nucleoprotein complexes located at the ends of chromosomes. In Human, telomeres consist of a T₂AG₃ repeated motif that shortens with each cell division throughout lifespan. Critically short telomeres lose their protective function and lead to cells senescence, apoptosis or early stages of cancer. Additionally, as telomeres shorten, changes in gene expression and epigenetic equilibrium are triggered in two ways: Telomere Position Effect (TPE) and Telomere Position Effect Over Long Distances (TPE-OLD). TPE is defined by the spreading of suppressive epigenetic marks over proximal genes whereas TPE-OLD is a phenomenon modulating transcription through 3D chromatin structure involving telomere sequences (DNA loops). We aimed to define TPE-OLD mechanisms and its implication in rare diseases. In order to achieve this, we developed two methods based on long read nanopore sequencing. The first one focuses on the establishment of telomere length on specific chromosomes, while at the same time identifying the methylation status of the subtelomere region (TPE analysis). The second method uses chromatin conformation capture techinques to visualize global TPE-OLD interactions. Altogether, our work holds the potential to reveal novel implication of telomeres in human pathologies. 

Encadrée par Igor Medyna