Abstract
FacioScapuloHumeral muscular Dystrophy (FSHD) is one of the most prevalent hereditary myopathies and is generally characterized by progressive muscle atrophy affecting the face, scapular fixators; upper arms and distal lower legs. The FSHD locus maps to a macrosatellite D4Z4 repeat array on chromosome 4q35. Each D4Z4 unit contains a DUX4 gene; the most distal of which is flanked by a polyadenylation site on FSHD-permissive alleles, which allows for production of stable DUX4 mRNAs. In addition, an open chromatin structure is required for DUX4 gene transcription. FSHD thus results from a gain of function of the toxic DUX4 protein that normally is only expressed in germ line and stem cells. Therapeutic strategies are emerging that aim to decrease DUX4 expression or toxicity in FSHD muscle cells. We review here the heterogeneity of DUX4 mRNAs observed in muscle and stem cells; and the use of antisense oligonucleotides (AOs) targeting the DUX4 mRNA to interfere either with transcript cleavage/polyadenylation or intron splicing. We show in primary cultures that DUX4-targeted AOs suppress the atrophic FSHD myotube phenotype; but do not improve the disorganized FSHD myotube phenotype which could be caused by DUX4c over-expression. Thus; DUX4c might constitute another therapeutic target in FSHD.
Highlights
In a search for target genes of the Helicase-Like Transcription Factor (HLTF) we serendipitously identified a promoter inserted in the 5’ part of this open reading frame (ORF) that reduced its size while maintaining the DoUble homeoboX (DUX) reading frame [17,18]
In the present article we review the use of antisense oligonucleotides (AOs) targeting the DUX4 mRNA as therapeutic agents in FacioScapuloHumeral muscular Dystrophy (FSHD)
We shall summarize the strategies established to interfere with either processing of the mRNA 3’ end or pre-mRNA splicing, and the regions that were targeted to develop specific AOs
Summary
FSHD is among the most common diseases of skeletal muscles and involves muscle atrophy, inflammation and oxidative stress [3,4]. Muscle symptoms may appear during childhood but most patients manifest the disease in their second or third decade. An asymmetric progressive muscle weakness begins with facial muscles. Genes 2017, 8, 93 causing eyelid drooping (ptosis), and an inability to whistle or smile [5]. These symptoms are missing in some patients. FSHD may commonly affect the shoulder girdle leading to the inability to raise arms above the shoulder line [6]. Triceps, or deltoid muscles are unequally affected
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