Facio-scapulo-humeral dystrophy (FSHD) results from deletions in the subtelomeric macrosatellite D4Z4 array on the 4q35 region. Upregulation of the DUX4 retrogene from the last D4Z4 repeated unit is thought to underlie FSHD pathophysiology. However, what triggers muscle defect and when alteration arises remains obscure. To gain further insights into the molecular mechanisms of the disease, the authors of the present study evaluated at the molecular level, the perturbation linked to the FSHD genotype with no a priori on disease onset, severity or penetrance and prior to any infiltration by fibrotic or adipose tissue in biopsies from foetuses carrying a short pathogenic D4Z4 array (n = 6) compared with foetuses with a non-pathogenic D4Z4 array (n = 21). By measuring expression of several muscle-specific markers and 4q35 genes including the DUX4 retrogene by an RT-PCR and western blotting, a global dysregulation of genes involved in myogenesis, including MYOD1 in samples with <11 D4Z4, was observed. The DUX4-fl pathogenic transcript was detected in FSHD biopsies but also in controls. Importantly, in FSHD foetuses, the non-spliced DUX4-fl isoform was mainly detected. In addition, several other genes clustered at the 4q35 locus are upregulated in FSHD foetuses. This is the first study to examine foetuses carrying an FSHD-linked genotype and reveals an extensive dysregulation of several muscle-specific and 4q35 genes at early development stage at a distance from any muscle defect. Overall, this work suggests that even if FSHD is an adult-onset muscular dystrophy, the disease might also involve early molecular defects arising during myogenesis or early differentiation.
