Facioscapulohumeral dystrophy (FSHD) is one of the most prevalent adult muscular dystrophies. The common clinical signs usually appear during the second decade of life but when the first molecular dysregulations occur is still unknown. Herein, the authors aimed to determine whether molecular dysregulations could be identified during FSHD foetal muscle development. Muscle biopsies from FSHD1 foetuses and the cells derived from some of these biopsies were compared with biopsies and cells from control foetuses. They focussed mainly on DUX4 isoform expression since the expression of DUX4 has been confirmed in both FSHD cells and biopsies by several laboratories. Isoform expression in treated or untreated foetal FSHD1 myotubes were measured by qRT-PCR DUX4 with a shRNA directed against DUX4 mRNA. DUX4 downstream target gene expression was also analysed in myotubes and foetal or adult FSHD1 and control quadriceps biopsies. It was demonstrated that both DUX4-FL isoforms are already expressed in FSHD1 myotubes. Interestingly, DUX4-FL expression level is much lower in trapezius than in quadriceps myotubes, which is confirmed by the level of expression of DUX4 downstream genes: The authors observed that TRIM43 and MBD3L2 are already over-expressed in FSHD1 foetal quadriceps biopsies, at similar levels to those observed in adult FSHD1 quadriceps biopsies. These results indicate that molecular markers of the disease are already expressed during foetal life, thus opening a new field of investigation for mechanisms leading to FSHD.
