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Muscle Disorders
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Kourosh Rezania, Peter Pytel, Betty Soliven
FSHD has been linked to genetic alterations in the subtelomeric portion of chromosome 4q35. This region normally contains 11 to over 100 so-called D4Z4 repeat elements.44 FSHD patients show a contraction in the number of these D4Z4 repeats to fewer than 11. This results in inefficient repression of a retrogene DUX4 and inappropriate DUX4 protein expression in muscle cells. The mechanisms underlying DUX4-induced muscle toxicity remain unclear. Patients with one to three repeats remaining may show most severe disease, but in contrast to nucleotide repeat diseases, there is no clear anticipation and no strong correlation between the number of repeats and the clinical phenotype. The change in D4Z4 repeats is thought to result in complex changes in gene expression rather than simply alteration of a single gene.
Neuromuscular disorders
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
The cause of the disease is inappropriate expression of DUX4, a gene on 4q that is usually repressed in muscle by subtelomeric repeats on 4q but which is transcribed inappropriately if deletion reduces the number of these repeats (FSHD1). Homology with subtelomeric repeats on 10q made the recognition of this pattern difficult to achieve and can make it more difficult to achieve accurate diagnostic results. In a small minority of patients (with FSHD2), the disease mechanism is mutation in a separate chromatin structural protein gene (SMCHD1) that is needed to regulate DUX4 in combination with a PAS (polyadenylation signal) on chromosome 4q. Inheritance is therefore digenic in FSHD2. Although complex, molecular tests are usually able to confirm the diagnosis and to enable prenatal diagnosis, although this is requested by only a minority of families.
Epigenetics from Oocytes to Embryos
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Dagnė Daškevičiūtė, Marta Sanchez-Delgado, David Monk
The first detection of transcription following fertilization occurs in the mouse zygote and is referred to as ZGA. This is unique among mammals as it occurs before the first cleavage division, with genome activation generally initiating in four- to eight-cell embryos and termed EGA (Figure 9.1b). Genome activation in the mouse is divided into the minor ZGA, occurring during the one-cell stage, and the major wave during the two-cell stage. The transcripts generated during the minor wave are rather promiscuous, low-level, and genome-wide, often resulting in transcripts that are inefficiently spliced and polyadenylated.62 Although the significance of the minor ZGA in the mouse remains unclear, and may reflect opportunistic transcription produced as the genomes are epigenetically reset, some significantly functional transcripts are produced. The D4Z4 repeats are located in the subtelomeric region of chr4q35 with each repeat unit containing the open reading frame for the DUX4 double-homeobox TF that acts as a transcriptional activator in both mice and humans.63 The D4Z4 repeats are normally highly methylated and enriched with H3K9me3, but during pre-implantation reprogramming, these marks are temporally depleted allowing for a burst of DUX4 expression.64,65 Chromatin immunoprecipitation experiments (ChIP-Seq) indicate that DUX preferentially binds to genes and endogenous retroviral elements (ERVs) that are specific for early stage embryos, with binding profiles overlapping intervals with chromatin accessibility.64 However, it is currently unknown if DUX acts as a pioneer factor, binding to heterochromatin and subsequently making it accessible, possibly through nucleosome remodeling and deposition of acetylation on histones.66 The DUX4 TF is not solely responsible for genome activation and other yet-to-be-identified pioneer factors/TFs must be involved. These may be maternally derived mRNAs that might be translationally upregulated, whereas others may be regulated at the level of transcription. In all cases, these early activators are not present at fertilization, suggesting their activity must be carefully controlled to prevent premature transcriptional activation.
The effects of 12 weeks’ resistance training on psychological parameters and quality of life in adults with Facioscapulohumeral, Becker, and Limb–girdle dystrophies
Published in Disability and Rehabilitation, 2022
Dawn N. O’Dowd, Emma L. Bostock, Dave Smith, Christopher I. Morse, Paul Orme, Carl J. Payton
Muscular dystrophy (MD) represents a heterogeneous group of neuromuscular conditions caused by mutations in various genes [1]. These mutations cause an absence or decrease in one of the many proteins typically located within the muscle cell [2], resulting in progressive muscle weakness and deterioration. The molecular basis of some MDs is better understood than others. Duchenne and Becker MD (BMD) exhibit an absence or reduced expression of the protein dystrophin in the plasma membrane of the muscle cell, respectively [2,3]. This causes instability within the cell membrane leaving muscle fibres susceptible to damage during contraction [4]. The molecular basis of Facioscapulohumeral MD (FSHD) was long debated but the consensus now exists that inappropriate expression of the protein DUX4 within skeletal muscle causes deterioration through mechanisms, such as apoptosis and diminished muscle regeneration [5,6]. No universal mechanism for muscle deterioration exists in Limb–girdle MD (LGMD) as it encompasses more than thirty subtypes. Each subtype affects a distinct protein within the sarcolemma, cytosol, or nucleus of the muscle cell, but it is probable that most LGMDs result in membrane instability akin to Duchenne and BMD [7]. FSHD, BMD, and LGMD differ in genotype and presentations of physical impairment, but each results in progressive reductions in muscle strength and physical function [8].