Estrogens enhance myoblast differentiation in facioscapulohumeral muscular dystrophy by antagonizing DUX4 activity

Teveroni, Emanuela; Pellegrino, Marsha; Sacconi, Sabrina; Calandra, Patrizia; Cascino, Isabella; Farioli-Vecchioli, Stefano; Puma, Angela; Garibaldi, Matteo; Morosetti, Roberta; Tasca, Giorgio; Ricci, Enzo; Trevisan, Carlo P.; Galluzzi, G.; Pontecorvi, Alfredo; Crescenzi, Marco; Deidda, G.; Moretti, Fabiola

doi:10.1172/jci89401

Cited by 52 publications

(41 citation statements)

References 54 publications

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“…In the current study we found no influence of sex on disease severity. Possible protective effects of antioxidants and female reproductive hormones are still under active investigation, but results are contradictory . One study on aerobic exercise in FSHD showed that it slows down disease progression in leg muscles …”

Section: Discussionsupporting

confidence: 91%

“…This study showed that the D4Z4 repeat array size (mainly) in the range from 5 to 9 repeat are contradictory. [28][29][30] One study on aerobic exercise in FSHD showed that it slows down disease progression in leg muscles. 31 The characteristic pattern of muscle involvement in FSHD prompted us to assess whether the influence of genetic and epigenetic factors differs per body region or muscle group.…”

Section: Discussionmentioning

confidence: 99%

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Phenotype‐genotype relations in facioscapulohumeral muscular dystrophy type 1

et al. 2018

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To determine how much of the clinical variability in facioscapulohumeral muscular dystrophy type 1 (FSHD1) can be explained by the D4Z4 repeat array size, D4Z4 methylation and familial factors, we included 152 carriers of an FSHD1 allele (23 single cases, 129 familial cases from 37 families) and performed state-of-the-art genetic testing, extensive clinical evaluation and quantitative muscle MRI. Familial factors accounted for 50% of the variance in disease severity (FSHD clinical score). The explained variance by the D4Z4 repeat array size for disease severity was limited (approximately 10%), and varied per body region (facial muscles, upper and lower extremities approximately 30%, 15% and 3%, respectively). Unaffected gene carriers had longer repeat array sizes compared to symptomatic individuals (7.3 vs 6.0 units, P = 0.000) and slightly higher Delta1 methylation levels (D4Z4 methylation corrected for repeat size, 0.96 vs -2.46, P = 0.048). The D4Z4 repeat array size and D4Z4 methylation contribute to variability in disease severity and penetrance, but other disease modifying factors must be involved as well. The larger effect of the D4Z4 repeat array on facial muscle involvement suggests that these muscles are more sensitive to the influence of the FSHD1 locus itself, whereas leg muscle involvement seems highly dependent on modifying factors.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Phenotype‐genotype relations in facioscapulohumeral muscular dystrophy type 1

et al. 2018

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“…On a molecular basis, a gender effect on methylation levels was not seen [15]. A recent study proposed an estrogen receptor as a potential disease modifier by interfering with DUX4 transcriptional activity [51], but further studies are necessary to investigate gender-specific disease effects.…”

Section: Disease Progressionmentioning

confidence: 98%

Facioscapulohumeral Muscular Dystrophy: Update on Pathogenesis and Future Treatments

Hamel

Tawil

2018

Neurotherapeutics

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A reliable model of a disease pathomechanism is the first step to develop targeted treatment. In facioscapulohumeral muscular dystrophy (FSHD), the third most common muscular dystrophy, recent advances in understanding the complex genetics and epigenetics have led to the identification of a disease mechanism, moving the field towards targeted therapy development. FSHD is caused by expression of DUX4, a retrogene located on the D4Z4 macrosatellite repeat array on chromosome 4q35, a gene expressed in the germline but typically repressed in somatic tissue. DUX4 derepression results from opening of the chromatin structure either by contraction of the number of repeats (FSHD1) or by chromatin hypomethylation of the D4Z4 repeats resulting from mutations in SMCHD1, a gene involved in chromatin methylation (FSHD2). The resulting expression of DUX4, a transcriptional regulator, and its target genes is toxic to skeletal muscle. Efforts for targeted treatment currently focus on disrupting DUX4 expression or blocking 1 or more of several downstream effects of DUX4. This review article focuses on the underlying FSHD genetics, current understanding of the pathomechanism, and potential treatment strategies in FSHD. In addition, recent advances in the development of new clinical outcome measures as well as biomarkers, critical for the success of future clinical trials, are reviewed.

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“…Sex differences in disease severity in FSHD patients have been observed in different studies, consistently reporting a higher proportion of women among asymptomatic gene carriers [5][6][7][8][9]. Additionally, cases have been reported of women experiencing a persistent worsening of symptoms following pregnancies, early menopause or anti-estrogenic therapy [10][11][12]. However, limited work has been done to systematically assess changes in disease progression during periods of pronounced hormonal changes.…”

Section: Introductionmentioning

confidence: 99%

Lifetime endogenous estrogen exposure and disease severity in female patients with facioscapulohumeral muscular dystrophy

Mul

Horlings

Voermans

et al. 2018

Neuromuscular Disorders

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Facioscapulohumeral muscular dystrophy (FSHD) is characterized by large variability in disease severity, that is only partly explained by (epi)genetic factors. Clinical observations and recent in vitro work suggest a protective effect of estrogens in FSHD. The aims of this study were to assess whether the lifetime endogenous estrogen exposure contributes to the variability in disease severity in female patients, and whether female patients experience changes in disease progression during periods of hormonal changes. We calculated the lifetime endogenous estrogen exposure by subtracting periods with high progesterone levels (in which estrogens are counteracted) from the reproductive life span. Multiple linear regression in 85 patients did not show a contribution of the lifetime endogenous estrogen exposure to disease severity (B = 0.063, P-value = 0.517, ΔR = 0.003). The majority of women reported an unchanged rate of disease progression through periods of hormonal changes, like menarche, pregnancy or menopause. Women that noticed differences reported accelerations as well as decelerations. These results indicate that differences in estrogen exposure do not have a clinically relevant modifying effect on disease severity. However, a clinically relevant protective effect of greater differences in estrogen levels, or a protective effect caused by a more complex interplay with other reproductive hormones, cannot be ruled out.

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Estrogens enhance myoblast differentiation in facioscapulohumeral muscular dystrophy by antagonizing DUX4 activity

Cited by 52 publications

References 54 publications

Phenotype‐genotype relations in facioscapulohumeral muscular dystrophy type 1

Phenotype‐genotype relations in facioscapulohumeral muscular dystrophy type 1

Facioscapulohumeral Muscular Dystrophy: Update on Pathogenesis and Future Treatments

Lifetime endogenous estrogen exposure and disease severity in female patients with facioscapulohumeral muscular dystrophy

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