Caveolar proteins: putative FSHD biomarkers?

Facioscapulohumeral dystrophy (FSHD) is a degenerative disease of skeletal muscle caused by chromatin opening and DNA hypomethylation at the D4Z4 repeat array in the 4q35 subtelomeric region. The open chromatin facilitates the expression of the DUX4 (Double Homeobox 4) gene that is located in the D4Z4 element. This gene encodes a transcription factor initiating a cascade of deregulation affecting many genes and that causes the disease.
Recently, our laboratory (in collaboration with Dpt of Proteomics and Microbiology UMONS) has compared the proteome of primary FSHD and control myotubes at day 4 of differentiation. Both FSHD myotube phenotypes presented a disturbance of several caveolar proteins such as PTRF (polymerase I and transcript release factor, cavin-1) and MURC (muscle-related coiled-coil protein, cavin-4). Caveolae are membrane nanodomains, often considered as a subset of lipid rafts, enriched in cholesterol and sphingolipids. They are also characterized by a specific protein composition. Caveolae play a major role in signal transduction and are involved in many biological processes. If caveolar dysfunction can be demonstrated in FSHD as suggested by our preliminary results, deregulation of MURC and PTRF proteins, that are essentials for membrane stability of skeletal muscle, could lead to deregulation of many cellular processes.
In addition, if a link between DUX4 and this caveolar dysfunction can be shown, these proteins could be used as additional FSHD biomarkers. Identification of FSHD biomarkers and their validation is essential to assess the therapeutic approach developed by our laboratory i.e. antisense tools preventing DUX4 expression.