Category Ranking
98%
Total Visits
921
Avg Visit Duration
2 minutes
Citations
20
Article Abstract
Objective: Facioscapulohumeral 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 gene in skeletal muscle. In this study, we tested the hypothesis whether , a known SMCHD1 protein interactor, is a disease gene for idiopathic FSHD2.
Methods: Clinical examination of a patient with idiopathic FSHD2 was combined with pathologic muscle biopsy examination and with genetic, epigenetic, and molecular studies.
Results: A homozygous 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 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 and DUX4 target gene expression.
Conclusion: 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 expression in skeletal muscle.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455367 | PMC |
| http://dx.doi.org/10.1212/WNL.0000000000009617 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
DUX4 at 25: how it emerged from "junk DNA" to become the cause of facioscapulohumeral muscular dystrophy.
Skelet Muscle
August 2025
Randall Centre for Cell and Molecular Biophysics, King's College London, Guy's Campus, London, SE1 1UL, UK.
Double Homeobox 4 (DUX4) is a potent transcription factor encoded by a retrogene mapped in D4Z4 repeated elements on chromosome 4q35. DUX4 has emerged as pivotal in the pathomechanisms of facioscapulohumeral muscular dystrophy (FSHD), a relatively common hereditary muscle wasting condition, although classified as a rare disease. DUX4 contributes to zygote genome activation before its expression is repressed in most somatic tissues through epigenetic mechanisms, including DNA methylation and chromatin modifications.
View Article and Find Full Text PDFNucleolar FRG2 lncRNAs inhibit rRNA transcription and cytoplasmic translation, linking FSHD to dysregulation of muscle-specific protein synthesis.
Nucleic Acids Res
July 2025
Department of Biomedical, Metabolic and Neural Sciences University of Modena and Reggio Emilia, Modena 41125, Italy.
Facioscapulohumeral muscular dystrophy (FSHD) is a hereditary myopathy linked to deletions of the tandemly arrayed D4Z4 macrosatellite at human chromosome 4q35. These deletions cause local chromatin changes and anomalous expression of nearby transcripts FRG2A, DBET, and D4Z4. We discovered that FRG2A is part of a family of long noncoding RNAs (lncRNAs) expressed in skeletal muscle cells, with levels varying among patients.
View Article and Find Full Text PDFPosttranscriptional RNA stabilization of telomeric RNAs FRG2, DBE-T, D4Z4 at human 4q35 in response to genotoxic stress and D4Z4 macrosatellite repeat length.
Clin Epigenetics
May 2025
Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Via G. Campi 287, 41125, Modena, Italy.
Background: Reduced copy number of the D4Z4 macrosatellite at human chromosome 4q35 is associated with facioscapulohumeral muscular dystrophy (FSHD). A pervasive idea is that chromatin alterations at the 4q35 locus following D4Z4 repeat unit deletion lead to disease via inappropriate expression of nearby genes. Here, we sought to analyze transcription and chromatin characteristics at specific regions of 4q35 and how these are affected by D4Z4 deletions and exogenous stresses.
View Article and Find Full Text PDF4qA D4Z4 Methylation Test as a Valuable Complement for Differential Diagnosis in Patients with a Facioscapulohumeral Muscular Dystrophy-Like Phenotype.
J Mol Diagn
May 2025
Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China; National Center for Neurological Disorder, Shanghai, China; Huashan Rare Disease Center, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China. Electronic address:
Facioscapulohumeral muscular dystrophy (FSHD) is caused by pleiotropic contractions of the D4Z4 repeat array on chromosome 4q35 (FSHD1) or by mutations in repressive chromatin regulators of the D4Z4 loci (FSHD2), both resulting in epigenetic dysregulation at the D4Z4 array. DNA methylation of the D4Z4 repeat array has been proposed for diagnosis and prognosis of FSHD disease severity; however, further validation in larger populations is needed. Two hundred forty-seven clinically suspected FSHD cases were retrospectively analyzed with D4Z4 analysis by optical genome mapping or molecular combing and tested the DNA methylation levels for 75 patients and 49 healthy controls.
View Article and Find Full Text PDFGermline mutations in SMCHD1, DNMT3B and LRIF1 can cause facioscapulohumeral muscular dystrophy type 2 (FSHD2). FSHD is an epigenetic skeletal muscle disorder in which partial failure in heterochromatinization of the D4Z4 macrosatellite repeat causes spurious expression of the repeat-embedded gene in skeletal muscle, ultimately leading to muscle weakness and wasting. All three proteins play a role in chromatin organization and gene silencing; however, their functional relationship has not been fully elucidated.
View Article and Find Full Text PDF