Does DNA Methylation Matter in FSHD?

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) has been associated with the genetic and epigenetic molecular features of the CpG-rich D4Z4 repeat tandem array at 4q35. Reduced DNA methylation of D4Z4 repeats is considered part of the FSHD mechanism and has been proposed as a reliable marker in the FSHD diagnostic procedure. We considered the assessment of D4Z4 DNA methylation status conducted on distinct cohorts using different methodologies. On the basis of the reported results we conclude that the percentage of DNA methylation detected at D4Z4 does not correlate with the disease status. Overall, data suggest that in the case of FSHD1, D4Z4 hypomethylation is a consequence of the chromatin structure present in the contracted allele, rather than a proxy of its function. Besides, CpG methylation at D4Z4 DNA is reduced in patients presenting diseases unrelated to muscle progressive wasting, like Bosma Arhinia and Microphthalmia syndrome, a developmental disorder, as well as ICF syndrome. Consistent with these observations, the analysis of epigenetic reprogramming at the D4Z4 locus in human embryonic and induced pluripotent stem cells indicate that other mechanisms, independent from the repeat number, are involved in the control of the epigenetic structure at D4Z4.

Control of DUX4 Expression in Facioscapulohumeral Muscular Dystrophy and Cancer

“…Thus, it is tempting to hypothesize that the hypomethylation of the D4Z4 array on chromosome 4 is one of the reasons underlying the FSHD pathology. Nevertheless, the methylation level of the D4Z4 array is highly variable in both healthy and FSHD1 individuals and seems to correlate with the number of D4Z4 units rather than the disease status (reviewed in [65]). In contrast, hypomethylation resulting from the SMCHD1 or DNMT3B mutations in FSHD2 seems to be the major cause of DUX4 derepression, though the strict correlation between SMCHD1/DNMT3B variants, the extent of D4Z4 hypomethylation and FSHD2 symptoms has not been established yet.…”

Cardiac Involvement in Facioscapulohumeral Muscular Dystrophy (FSHD)

“…The D4Z4 contraction leads to translational de-repression of DUX4 ( 3 ). This is generally thought to result from hypomethylation of the D4Z4 repeats, though some studies have questioned this view ( 4 , 5 ). There is also evidence that additional genetic mechanisms play a role in the development of FSHD ( 6 , 7 ).…”

The Italian National Registry for FSHD: an enhanced data integration and an analytics framework towards Smart Health Care and Precision Medicine for a rare disease

“…FSHD is considered an autosomal dominant disorder, associated with rearrangements occurring in a 3.3 kilobase (kb) tandemly repeated sequence (D4Z4) located at the 4q subtelomere [5]. The analysis of FSHD penetrance [3,[6][7][8][9][10][11][12][13][14] reinforced the idea that additional elements take part in disease onset and progression. Indeed, the clinical variability and non-penetrance observed in presence of the same molecular defect affect diagnosis, prognosis, genetic counseling.…”