FRG2, an FSHD candidate gene, is transcriptionally upregulated in differentiating primary myoblast cultures of FSHD patients

Rijkers, Tonnie; Deidda, G.; Koningsbruggen, Silvana van; Geel, Michel van; Lemmers, Richard J.L.F.; Deutekom, J.C.T. van; Figlewicz, Denise A.; Hewitt, Jane; Padberg, George W.; Frants, Rune R.; Maarel, Silvère M. van der

doi:10.1136/jmg.2004.019364

Cited by 76 publications

(78 citation statements)

References 47 publications

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“…27 In contrast, previous studies have reported that FRG2 mRNA in differentiated cultures of FSHD, but not unaffected cells, and not at all in proliferating cultures. 12,26 The reasons behind these discrepancies remain to be determined, but the very low level of FRG2 expression and different qPCR assays might contribute. Also unlike previous studies, 14,16 we found no difference between FSHD and unaffected cells in responses to paraquat or hydrogen peroxide.…”

Section: Discussionmentioning

confidence: 99%

A unique library of myogenic cells from facioscapulohumeral muscular dystrophy subjects and unaffected relatives: family, disease and cell function

et al. 2011

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To explore possible mechanisms of pathology in facioscapulohumeral muscular dystrophy (FSHD), we generated a novel library of myogenic cells composed of paired cultures derived from FSHD subjects and unaffected first-degree relatives. We prepared cells from biopsies of both biceps and deltoid muscles obtained from each of 10 FSHD and 9 unaffected donors. We used this new collection to determine how family background and disease affected patterns of growth and differentiation, expression of a panel of candidate, and muscle-specific genes, and responses to exogenous stressors. We found that FSHD and unaffected cells had, on average, indistinguishable patterns of differentiation, gene expression, and dose-response curves to staurosporine, paraquat, hydrogen peroxide, and glutathione depletion. Differentiated FSHD and unaffected cultures were both more sensitive to glutathione depletion than proliferating cultures, but showed similar responses to paraquat, staurosporine, and peroxide. For stress responses, the sample size was sufficient to detect a 10% change in effect at the observed variability with a power of 499%. In contrast, for each of these properties, we found significant differences among cells from different cohorts, and these differences were independent of disease status, gender, or muscle biopsied. Thus, though none of the properties we examined could be used to reliably distinguish between FSHD and unaffected cells, family of origin was an important contributor to gene-expression patterns and stressor responses in cultures of both FSHD and unaffected myogenic cells.

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Section: Discussionmentioning

confidence: 99%

A unique library of myogenic cells from facioscapulohumeral muscular dystrophy subjects and unaffected relatives: family, disease and cell function

et al. 2011

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“…Indeed, closely located genes such as FSHD Region Gene 2 (FRG2), FSHD Region Gene 1 (FRG1), and Adenine Nucleotide Translocator (ANT1), with high myopathic potential, were observed to be transcriptionally upregulated in FSHD muscle (Gabellini et al, 2002). However, studies testing this model obtained conflicting results with some showing support (Gabellini et al, 2002;Rijkers et al, 2004;Klooster et al, 2009;Bodega et al, 2009), and others not (Winokur et al, 2003b;Jang et al, 2003;Osborne et al, 2007;Masny et al, 2010). These discrepancies prevented a general consensus on the role of 4q35 genes upregulation in FSHD pathogenesis.…”

Section: Introductionmentioning

confidence: 87%

“…The FRG2 ORF encodes a putative protein of 278 amino acids. The FRG2 protein does not show significant homology to known proteins (Rijkers et al, 2004). Alternative splicing creates an additional alanine codon (Rijkers et al, 2004).…”

Section: Fshd Region Gene 2 (Frg2)mentioning

confidence: 99%

“…The FRG2 protein does not show significant homology to known proteins (Rijkers et al, 2004). Alternative splicing creates an additional alanine codon (Rijkers et al, 2004). Even though FRG2 has been shown to be nuclear, (Rijkers et al, 2004) its sequence contains not only two potential nuclear localization signals (NLS) but also a peroxisomal targeting signal (PTS1) at the carboxyterminal end of the protein (Swinkels et al, 1992).…”

Section: Fshd Region Gene 2 (Frg2)mentioning

confidence: 99%

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Facioscapulohumeral Muscular Dystrophy: From Clinical Data to Molecular Genetics and Return

Salani¹,

Morini²,

Scionti³

et al. 2012

Neuromuscular Disorders

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“…FRG2B is homologous to FRG2 located on chromosome 4, which has been implicated in playing a role in the pathogenesis of facioscapulohumeral muscular dystrophy (FSHD) in patients with substantial reductions in a 11-150 unit 4q35 microsatellite repeat [67][68][69]. However, reductions in the homologous 10qt26 microsatellite repeat, proximal to FRG2B, have not been associated with FSHD.…”

Section: A Taf1 Variant Implicated In Disease Phenotypementioning

confidence: 99%

A variant inTAF1is associated with a new syndrome with severe intellectual disability and characteristic dysmorphic features

Lyon

2015

Preprint

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We describe the discovery of a new genetic syndrome, RykDax syndrome, driven by a whole genome sequencing (WGS) study of one family from Utah with two affected male brothers, presenting with severe intellectual disability (ID), a characteristic intergluteal crease, and very distinctive facial features including a broad, upturned nose, sagging cheeks, downward sloping palpebral fissures, prominent periorbital ridges, deep-set eyes, relative hypertelorism, thin upper lip, a high-arched palate, prominent ears with thickened helices, and a pointed chin. This Caucasian family was recruited from Utah, USA. Illumina-based WGS was performed on 10 members of this family, with additional Complete Genomics-based WGS performed on the nuclear portion of the family (mother, father and the two affected males). Using WGS datasets from 10 members of this family, we can increase the reliability of the biological inferences with an integrative bioinformatic pipeline. In combination with insights from clinical evaluations and medical diagnostic analyses, these DNA sequencing data were used in the study of three plausible genetic disease models that might uncover genetic contribution to the syndrome. We found a 2 to 5-fold difference in the number of variants detected as being relevant for various disease models when using different sets of sequencing data and analysis pipelines. We derived greater accuracy when more pipelines were used in conjunction with data encompassing a larger portion of the family, with the number of putative de-novo mutations being reduced by 80%, due to false negative calls in the parents. The boys carry a maternally inherited missense variant in a X-chromosomal gene TAF1, which we consider as disease relevant. TAF1 is the largest subunit of the general transcription factor IID (TFIID) multi-protein complex, and our results implicate mutations in TAF1 as playing a critical role in the development of this new intellectual disability syndrome.

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FRG2, an FSHD candidate gene, is transcriptionally upregulated in differentiating primary myoblast cultures of FSHD patients

Cited by 76 publications

References 47 publications

A unique library of myogenic cells from facioscapulohumeral muscular dystrophy subjects and unaffected relatives: family, disease and cell function

A unique library of myogenic cells from facioscapulohumeral muscular dystrophy subjects and unaffected relatives: family, disease and cell function

Facioscapulohumeral Muscular Dystrophy: From Clinical Data to Molecular Genetics and Return

A variant inTAF1is associated with a new syndrome with severe intellectual disability and characteristic dysmorphic features

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