Facioscapulohumeral muscular dystrophy: genetics, gene activation and downstream signalling with regard to recent therapeutic approaches: an update

Whilst a disease-modifying treatment for Facioscapulohumeral muscular dystrophy (FSHD) does not exist currently, recent advances in complex molecular pathophysiology studies of FSHD have led to possible therapeutic approaches for its targeted treatment. Although the underlying genetics of FSHD have...

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Bibliographic Details
Published in:Orphanet journal of rare diseases 2021-03, Vol.16 (1), p.129-26, Article 129
Main Authors: Schätzl, Teresa, Kaiser, Lars, Deigner, Hans-Peter
Format: Article
Language:English
Subjects:
Care and treatment
Cell death
Chromosome 4
Chromosomes
Contraction
Development and progression
Disease
Double Homeobox 4 (DUX4)
Downstream signalling
Ectopic expression
Epigenetic
Epigenetics
Facioscapulohumeral muscular dystrophy
Facioscapulohumeral muscular dystrophy (FSHD)
Gene expression
Genetic aspects
Genetics
Genotype & phenotype
Homeodomain Proteins - genetics
Humans
Medical research
Muscle, Skeletal - metabolism
Muscular dystrophy
Muscular Dystrophy, Facioscapulohumeral - genetics
Mutation
Pathophysiology
Quality of life
Rare diseases
Review
Signal Transduction
Skeletal muscle
Social research
Transcription
Transcriptional Activation
Treatment strategies
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Summary:Whilst a disease-modifying treatment for Facioscapulohumeral muscular dystrophy (FSHD) does not exist currently, recent advances in complex molecular pathophysiology studies of FSHD have led to possible therapeutic approaches for its targeted treatment. Although the underlying genetics of FSHD have been researched extensively, there remains an incomplete understanding of the pathophysiology of FSHD in relation to the molecules leading to DUX4 gene activation and the downstream gene targets of DUX4 that cause its toxic effects. In the context of the local proximity of chromosome 4q to the nuclear envelope, a contraction of the D4Z4 macrosatellite induces lower methylation levels, enabling the ectopic expression of DUX4. This disrupts numerous signalling pathways that mostly result in cell death, detrimentally affecting skeletal muscle in affected individuals. In this regard different options are currently explored either to suppress the transcription of DUX4 gene, inhibiting DUX4 protein from its toxic effects, or to alleviate the symptoms triggered by its numerous targets.
ISSN:1750-1172
1750-1172
DOI:10.1186/s13023-021-01760-1