Facioscapulohumeral muscular dystrophy 1 patients participating in the UK FSHD registry can be subdivided into 4 patterns of self-reported symptoms

Banerji, Christopher R. S.; Cammish, P.; Evangelista, Teresinha; Zammit, Peter S.; Straub, V.; Marini‐Bettolo, Chiara

doi:10.1016/j.nmd.2020.03.001

Cited by 16 publications

(21 citation statements)

References 43 publications

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“…MVC of TA (Ricci score vs MVC of TA: Pearson’s r =-0.53, p =0.011; Lamperti score vs MVC of TA: Pearson’s r =-0.52, p =0.013; MRC sum score vs MVC of TA: Pearson’s r =0.62, p =0.0022, Figure 1 ), as well as with LLFF (Ricci score vs LLFF: Pearson’s r =0.61, p =0.0013; Lamperti score vs LLFF: Pearson’s r =0.60, p =0.0016; MRC sum score vs LLFF: Pearson’s r =0.63, p =7.4×10 −4 , Figure 1 ). D4Z4 repeat length was inversely associated with LLFF (Pearson’s r =-0.57, p =0.0037, Figure 1 ), consistent with known association between shorter D4Z4 repeat lengths and more severe pathology 30 , although not with Ricci, Lamperti, MRC sum score nor MVC of TA. Self-reported FSHD disease duration did not correlate with any other markers of clinical severity ( Figure 1 ).…”

Section: Resultssupporting

confidence: 78%

A circulating biomarker of facioscapulohumeral muscular dystrophy clinical severity, valid in skeletal muscle and blood

Banerji

Grecco

Joosten

et al. 2022

Preprint

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Facioscapulohumeral muscular dystrophy (FSHD) is incurable. DUX4 mis-expression is believed to underlie FSHD pathogenesis, alongside PAX7 target gene repression, yet clinical trials lack robust biomarkers of severity. FSHD entails fatty replacement of muscle, accelerated by inflammation, we thus performed RNA-sequencing on both an MRI guided inflamed (TIRM+) and non-inflamed (TIRM-) muscle biopsies from clinically-characterised FSHD patients, alongside peripheral blood mononucleated cells (PBMCs). PAX7 target gene repression in TIRM- muscle associates with severity. DUX4 target gene biomarkers associate with lower limb fat fraction and D4Z4 repeat length, but not severity. PAX7 target gene repression in muscle correlates with levels in matched PBMCs. A refined biomarker computed in PBMCs associates with severity in FSHD patients, and also validates as a classifier of severity in an independent set of 54 FSHD patient blood samples. In summary, we present a minimally-invasive, circulating, transcriptomic biomarker of FSHD clinical severity valid in muscle and blood.

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Section: Resultssupporting

confidence: 78%

A circulating biomarker of facioscapulohumeral muscular dystrophy clinical severity, valid in skeletal muscle and blood

Banerji

Grecco

Joosten

et al. 2022

Preprint

Self Cite

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“…Well documented is a facial sparing variant that associates with longer D4Z4 repeat length (Felice et al , 2000 ; Ricci et al , 2019 ). Rarer phenotypes include earlier lower limb muscle weakness, and milder involvement of facial and shoulder girdle muscles demonstrated in a UK population on the UK FSHD Patient Registry (Ricci et al , 2019 ; Banerji et al , 2020a ) and confirmed in a US population on the National Registry for Myotonic Dystrophy (DM) and Facioscapulohumeral Dystrophy (FSHD) (unpublished data).…”

Section: Clinical Features Of Fshdmentioning

confidence: 86%

“…The earliest clinical sign is often facial weakness in the orbicularis oculi and orbicularis oris (Fig 1 ), although such facial weakness is often reported later in life as it presents with typically unobtrusive symptoms, such as difficulty whistling and incomplete eye closure during sleep. The most common presenting symptom (~ 70% of patients) is weak shoulder abduction and scapular winging derived from weakness of latissimus dorsi, serratus anterior, pectoralis, subscapularis, rhomboids and, later, trapezius (Tyler & Stephens, 1950 ; Ricci et al , 2013 ; Tawil et al , 2014 ; Banerji et al , 2020a ). The humeral component entails weakening of the biceps brachii, typically presenting at/after onset of shoulder girdle weakness.…”

Section: Clinical Features Of Fshdmentioning

confidence: 99%

Pathomechanisms and biomarkers in facioscapulohumeral muscular dystrophy: roles of DUX4 and PAX7

Banerji

Zammit

2021

EMBO Mol Med

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Facioscapulohumeral muscular dystrophy (FSHD) is characterised by progressive skeletal muscle weakness and wasting. FSHD is linked to epigenetic derepression of the subtelomeric D4Z4 macrosatellite at chromosome 4q35. Epigenetic derepression permits the distal‐most D4Z4 unit to transcribe DUX4, with transcripts stabilised by splicing to a poly(A) signal on permissive 4qA haplotypes. The pioneer transcription factor DUX4 activates target genes that are proposed to drive FSHD pathology. While this toxic gain‐of‐function model is a satisfying “bottom‐up” genotype‐to‐phenotype link, DUX4 is rarely detectable in muscle and DUX4 target gene expression is inconsistent in patients. A reliable biomarker for FSHD is suppression of a target gene score of PAX7, a master regulator of myogenesis. However, it is unclear how this “top‐down” finding links to genomic changes that characterise FSHD and to DUX4. Here, we explore the roles and interactions of DUX4 and PAX7 in FSHD pathology and how the relationship between these two transcription factors deepens understanding via the immune system and muscle regeneration. Considering how FSHD pathomechanisms are represented by “DUX4opathy” models has implications for developing therapies and current clinical trials.

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“…Our finding would contribute to the understanding of the normal role of DUX4 in early embryo development, adult tissue expression (i.e., gonadal, thymus and skin), and the pathogenesis of FSHD. Eventually, they could contribute to explain the biochemical mechanism(s) connecting abnormal DUX4 expression with the gender differences observed in the FSHD phenotype [56][57][58][59][60][61] and/or the inflammatory pathology observed in muscles of FSHD patients [62][63][64][65][66][67][68], both clinical phenotypes associated to the endocrine system.…”

Section: Discussionmentioning

confidence: 99%

The DUX4 protein is a co‐repressor of the progesterone and glucocorticoid nuclear receptors

Quintero

Saad

Pagnoni³

et al. 2022

FEBS Letters

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DUX4 is a transcription factor required during early embryonic development in placental mammals. In this work, we provide evidence that DUX4 is a co‐repressor of nuclear receptors (NRs) of progesterone (PR) and glucocorticoids (GR). The DUX4 C‐ter and N‐ter regions, including the nuclear localization signals and homeodomain motifs, contribute to the co‐repressor activity of DUX4 on PR and GR. Immunoprecipitation studies, using total protein extracts of cells expressing tagged versions of DUX4 and GR, support that these proteins are physically associated. Our studies suggest that DUX4 could modulate gene expression by co‐regulating the activity of hormone NRs. This is the first report highlighting a potential endocrine role for DUX4.

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Facioscapulohumeral muscular dystrophy 1 patients participating in the UK FSHD registry can be subdivided into 4 patterns of self-reported symptoms

Cited by 16 publications

References 43 publications

A circulating biomarker of facioscapulohumeral muscular dystrophy clinical severity, valid in skeletal muscle and blood

A circulating biomarker of facioscapulohumeral muscular dystrophy clinical severity, valid in skeletal muscle and blood

Pathomechanisms and biomarkers in facioscapulohumeral muscular dystrophy: roles of DUX4 and PAX7

The DUX4 protein is a co‐repressor of the progesterone and glucocorticoid nuclear receptors

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