The Fragile X Mental Retardation-Related 1 (FXR1) gene belongs to the Fragile X Related family, that also include the Fragile X Mental retardation (FMR1) gene involved in Fragile X syndrome, the most common form of inherited mental retardation. While the absence of FMRP impairs cognitive functions, inactivation of FXR1 has been reported to have drastic effects in mouse and xenopus myogenesis. Seven alternatively spliced FXR1 mRNA variants have been identified, three of them being muscle-specific. Interestingly, they encode FXR1P isoforms displaying selective RNA-binding properties. Since Facio-ScapuloHumeral muscular Dystrophy (FSHD) is an inherited myopathy characterized by altered splicing of mRNAs encoding muscle-specific proteins, we have studied the splicing pattern of FXR1 mRNA in myoblasts and myotubes of FSHD patients. We show here that FSHD-affected myoblasts display an abnormal pattern of expression of FXR1P isoforms. Moreover, we provide evidence that this altered pattern of expression is due to a specific reduced stability of muscle-specific FXR1 mRNA variants, leading to a reduced expression of FXR1P muscle-specific isoforms. Our data suggest that the molecular basis of FSHD not only involves splicing alterations, as previously proposed, but may also involve a deregulation of mRNA stability. In addition, since FXR1P is an RNA-binding protein likely to regulate the metabolism of muscle-specific mRNAs during myogenesis, its altered expression in FSHD myoblasts may contribute to the physiopathology of this disease.