scholarly journals DUX4 Signalling in the Pathogenesis of Facioscapulohumeral Muscular Dystrophy

2020 ◽  
Vol 21 (3) ◽  
pp. 729 ◽  
Author(s):  
Kenji Rowel Q. Lim ◽  
Quynh Nguyen ◽  
Toshifumi Yokota
Keyword(s):  
Skeletal Muscle ◽  
Cell Death ◽  
Transcription Factor ◽  
Muscular Dystrophy ◽  
Embryonic Development ◽  
Disease Onset ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Signalling Pathways ◽  
Progressive Muscle Weakness ◽  
Homeobox Protein

Facioscapulohumeral muscular dystrophy (FSHD) is a disabling inherited muscular disorder characterized by asymmetric, progressive muscle weakness and degeneration. Patients display widely variable disease onset and severity, and sometimes present with extra-muscular symptoms. There is a consensus that FSHD is caused by the aberrant production of the double homeobox protein 4 (DUX4) transcription factor in skeletal muscle. DUX4 is normally expressed during early embryonic development, and is then effectively silenced in all tissues except the testis and thymus. Its reactivation in skeletal muscle disrupts numerous signalling pathways that mostly converge on cell death. Here, we review studies on DUX4-affected pathways in skeletal muscle and provide insights into how understanding these could help explain the unique pathogenesis of FSHD.

scholarly journals DUX4 Role in Normal Physiology and in FSHD Muscular Dystrophy

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3322
Author(s):  
Emanuele Mocciaro ◽  
Valeria Runfola ◽  
Paola Ghezzi ◽  
Maria Pannese ◽  
Davide Gabellini
Keyword(s):  
Muscular Dystrophy ◽  
Embryonic Development ◽  
Transcriptional Activation ◽  
Current Knowledge ◽  
Relevant Information ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Healthy Humans ◽  
Somatic Tissues ◽  
Key Factor ◽  
Development Regulation

In the last decade, the sequence-specific transcription factor double homeobox 4 (DUX4) has gone from being an obscure entity to being a key factor in important physiological and pathological processes. We now know that expression of DUX4 is highly regulated and restricted to the early steps of embryonic development, where DUX4 is involved in transcriptional activation of the zygotic genome. While DUX4 is epigenetically silenced in most somatic tissues of healthy humans, its aberrant reactivation is associated with several diseases, including cancer, viral infection and facioscapulohumeral muscular dystrophy (FSHD). DUX4 is also translocated, giving rise to chimeric oncogenic proteins at the basis of sarcoma and leukemia forms. Hence, understanding how DUX4 is regulated and performs its activity could provide relevant information, not only to further our knowledge of human embryonic development regulation, but also to develop therapeutic approaches for the diseases associated with DUX4. Here, we summarize current knowledge on the cellular and molecular processes regulated by DUX4 with a special emphasis on FSHD muscular dystrophy.

scholarly journals Homozygous nonsense variant in LRIF1 associated with facioscapulohumeral muscular dystrophy

Neurology ◽  
2020 ◽  
Vol 94 (23) ◽  
pp. e2441-e2447 ◽  
Author(s):  
Kohei Hamanaka ◽  
Darina Šikrová ◽  
Satomi Mitsuhashi ◽  
Hiroki Masuda ◽  
Yukari Sekiguchi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Target Gene ◽  
Disease Gene ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Target Gene Expression ◽  
D4z4 Repeat ◽  
Biopsy Examination ◽  
Chromatin Relaxation

ObjectiveFacioscapulohumeral muscular dystrophy (FSHD) is a heterogenetic disorder predominantly characterized by progressive facial and scapular muscle weakness. Patients with FSHD either have a contraction of the D4Z4 repeat on chromosome 4q35 or mutations in D4Z4 chromatin modifiers SMCHD1 and DNMT3B, both causing D4Z4 chromatin relaxation and inappropriate expression of the D4Z4-encoded DUX4 gene in skeletal muscle. In this study, we tested the hypothesis whether LRIF1, a known SMCHD1 protein interactor, is a disease gene for idiopathic FSHD2.MethodsClinical examination of a patient with idiopathic FSHD2 was combined with pathologic muscle biopsy examination and with genetic, epigenetic, and molecular studies.ResultsA homozygous LRIF1 mutation was identified in a patient with a clinical phenotype consistent with FSHD. This mutation resulted in the absence of the long isoform of LRIF1 protein, D4Z4 chromatin relaxation, and DUX4 and DUX4 target gene expression in myonuclei, all molecular and epigenetic hallmarks of FSHD. In concordance, LRIF1 was shown to bind to the D4Z4 repeat, and knockdown of the LRIF1 long isoform in muscle cells results in DUX4 and DUX4 target gene expression.ConclusionLRIF1 is a bona fide disease gene for FSHD2. This study further reinforces the unifying genetic mechanism, which postulates that FSHD is caused by D4Z4 chromatin relaxation, resulting in inappropriate DUX4 expression in skeletal muscle.

scholarly journals Applying genome-wide CRISPR-Cas9 screens for therapeutic discovery in facioscapulohumeral muscular dystrophy

2020 ◽  
Vol 12 (536) ◽  
pp. eaay0271 ◽  
Author(s):  
Angela Lek ◽  
Yuanfan Zhang ◽  
Keryn G. Woodman ◽  
Shushu Huang ◽  
Alec M. DeSimone ◽  
...  
Keyword(s):  
Cell Death ◽  
Muscular Dystrophy ◽  
Phenotypic Selection ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Loss Of Function ◽  
Hypoxia Response ◽  
Genome Wide ◽  
A Genome ◽  
Structural And Functional Properties ◽  
Cellular Hypoxia

The emergence of CRISPR-Cas9 gene-editing technologies and genome-wide CRISPR-Cas9 libraries enables efficient unbiased genetic screening that can accelerate the process of therapeutic discovery for genetic disorders. Here, we demonstrate the utility of a genome-wide CRISPR-Cas9 loss-of-function library to identify therapeutic targets for facioscapulohumeral muscular dystrophy (FSHD), a genetically complex type of muscular dystrophy for which there is currently no treatment. In FSHD, both genetic and epigenetic changes lead to misexpression of DUX4, the FSHD causal gene that encodes the highly cytotoxic DUX4 protein. We performed a genome-wide CRISPR-Cas9 screen to identify genes whose loss-of-function conferred survival when DUX4 was expressed in muscle cells. Genes emerging from our screen illuminated a pathogenic link to the cellular hypoxia response, which was revealed to be the main driver of DUX4-induced cell death. Application of hypoxia signaling inhibitors resulted in increased DUX4 protein turnover and subsequent reduction of the cellular hypoxia response and cell death. In addition, these compounds proved successful in reducing FSHD disease biomarkers in patient myogenic lines, as well as improving structural and functional properties in two zebrafish models of FSHD. Our genome-wide perturbation of pathways affecting DUX4 expression has provided insight into key drivers of DUX4-induced pathogenesis and has identified existing compounds with potential therapeutic benefit for FSHD. Our experimental approach presents an accelerated paradigm toward mechanistic understanding and therapeutic discovery of a complex genetic disease, which may be translatable to other diseases with well-established phenotypic selection assays.

scholarly journals A feedback loop between nonsense-mediated decay and the retrogene DUX4 in facioscapulohumeral muscular dystrophy

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Qing Feng ◽  
Lauren Snider ◽  
Sujatha Jagannathan ◽  
Rabi Tawil ◽  
Silvère M van der Maarel ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Muscular Dystrophy ◽  
Feedback Loop ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Proteolytic Degradation ◽  
Central Component ◽  
Double Negative ◽  
Nonsense Mediated Decay ◽  
Homeobox Transcription Factor ◽  
Epigenetic Repression

Facioscapulohumeral muscular dystrophy (FSHD) is a muscular dystrophy caused by inefficient epigenetic repression of the D4Z4 macrosatellite array and somatic expression of the DUX4 retrogene. DUX4 is a double homeobox transcription factor that is normally expressed in the testis and causes apoptosis and FSHD when misexpressed in skeletal muscle. The mechanism(s) of DUX4 toxicity in muscle is incompletely understood. We report that DUX4-triggered proteolytic degradation of UPF1, a central component of the nonsense-mediated decay (NMD) machinery, is associated with profound NMD inhibition, resulting in global accumulation of RNAs normally degraded as NMD substrates. DUX4 mRNA is itself degraded by NMD, such that inhibition of NMD by DUX4 protein stabilizes DUX4 mRNA through a double-negative feedback loop in FSHD muscle cells. This feedback loop illustrates an unexpected mode of autoregulatory behavior of a transcription factor, is consistent with ‘bursts’ of DUX4 expression in FSHD muscle, and has implications for FSHD pathogenesis.

scholarly journals Case Reports: Emery-Dreifuss Muscular Dystrophy Presenting as a Heart Rhythm Disorders in Children

2021 ◽  
Vol 8 ◽  
Author(s):  
Tatiana Kovalchuk ◽  
Elena Yakovleva ◽  
Svetlana Fetisova ◽  
Tatiana Vershinina ◽  
Viktoriya Lebedeva ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Case Reports ◽  
Sinus Node ◽  
Heart Rhythm ◽  
Cardiac Abnormalities ◽  
Progressive Muscle Weakness ◽  
Cardiac Phenotype ◽  
Cardiac Symptoms ◽  
Heart Rhythm Disorders

Emery-Dreifuss muscular dystrophy (EDMD) is inherited muscle dystrophy often accompanied by cardiac abnormalities in the form of supraventricular arrhythmias, conduction defects and sinus node dysfunction. Cardiac phenotype typically arises years after skeletal muscle presentation, though, could be severe and life-threatening. The defined clinical manifestation with joint contractures, progressive muscle weakness and atrophy, as well as cardiac symptoms are observed by the third decade of life. Still, clinical course and sequence of muscle and cardiac signs may be variable and depends on the genotype. Cardiac abnormalities in patients with EDMD in pediatric age are not commonly seen. Here we describe five patients with different forms of EDMD (X-linked and autosomal-dominant) caused by the mutations in EMD and LMNA genes, presented with early onset of cardiac abnormalities and no prominent skeletal muscle phenotype. The predominant forms of cardiac pathology were atrial arrhythmias and conduction disturbances that progress over time. The presented cases discussed in the light of therapeutic strategy, including radiofrequency ablation and antiarrhythmic devices implantation, and the importance of thorough neurological and genetic screening in pediatric patients presenting with complex heart rhythm disorders.

P.41Extra-skeletal muscle manifestations of facioscapulohumeral muscular dystrophy

2019 ◽  
Vol 29 ◽  
pp. S53
Author(s):  
C. Kelly ◽  
J. Saw ◽  
P. Thapa ◽  
J. Mandrekar ◽  
E. Naddaf
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Facioscapulohumeral Muscular Dystrophy
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