An epigenetic basis for genetic anticipation in facioscapulohumeral muscular dystrophy type 1

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by marked inter- and intrafamilial heterogeneity in its clinical expression. The contribution of genetic factors to this variability is not well characterized. We examined the relationship of phenotype to genotype in a clinically and genetically well-defined FSHD population. Quantitative isometric myometry (QMT) scores, normalized for age, gender, and height, were used to quantify disease severity. We found a significant (r = 0.92, p < 0.004) correlation between disease severity and the size of the 4q35-associated deletion. In addition, when relative disease severity of parent-offspring pairs was compared, the offspring were found to be significantly more severely affected (p = 0.011). This generational effect suggests the presence of anticipation in FSHD and raises the possibility of an underlying dynamic mutation.

DNA methylation has been acknowledged as one of the key epigenetic mechanisms involved in the regulation of gene expression and genomic functions. Alteration of the DNA methylation level has been linked to modification of the disease progression and instability regulation of certain disease-causing repeats in neurodegenerative diseases. In this study, blood samples collected from spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) patients versus control were used to explore the potential link of DNA methylation levels at ATXN3 gene promoter to the pathogenesis of SCA3/MJD. We found that the methylation levels in the ATXN3 promoter were significantly higher in SCA3/MJD patients relative to the controls. Furthermore, higher methylation levels were detected in the SCA3/MJD patients with earlier age at onset and the families with an intergenerational CAG repeats instability. In addition, the first CpG island of the ATXN3 promoter served as the main regulation region of DNA methylation. These findings suggested that an epigenetic change may contribute to the pathogenesis of the SCA3/MJD and provide potential therapeutic targets for CAG repeats-based diseases.