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.
Highlights
Facioscapulohumeral muscular dystrophy (FSHD, OMIM#158900) is the third most common myopathy with a reported prevalence ranging between 1 in 8333 [1] and 1 in 20,000 [2]
FSHD1 and, at a greater extent, FSHD2 patients present D4Z4 DNA hypomethylation [33,48,49]. All these findings supported the hypothesis that significant alteration of the 4q35 epigenetic landscape is central to FSHD, and that this occurs in FSHD1 by removal of a significant number of D4Z4 heterochromatic elements, and in FSHD2, via SMCHD1 or DNMT3B haploinsufficiency in presence of a specific telomeric polymorphism, 4qA, which allows the expression of the most distal copy of the
Further investigations are required to answer a few important questions, such as the role of epigenetic alterations in FSHD, whether hypomethylation leads to DUX4 activation and, above all, how this translates into a specific muscle phenotype
Summary
Facioscapulohumeral muscular dystrophy (FSHD, OMIM#158900) is the third most common myopathy with a reported prevalence ranging between 1 in 8333 [1] and 1 in 20,000 [2]. The routine DNA molecular testing, based on the identification of D4Z4 arrays with less than 10 genotype–phenotype studies have shown that D4Z4 reduction (4–8 reduced units, RU) is present units at 4q35, has been considered highly sensitive and specific [23,24]. D4Z4 alleles the general population [25,26,27,28] and in some cases is associated with distinct myopathic phenotypes of borderline size All this has All relevant effects among relatives carrying same D4Z4 allele [7,9,10,12,25,34,35] This has on clinical practice, diagnosis, prognosis, and genetic counseling.
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