Alteration of expression of muscle specific isoforms of the fragile X related protein 1 (FXR1P) in facioscapulohumeral muscular dystrophy patients

Davidovic, Laetitia; Sacconi, Sabrina; Bechara, Elías; Delplace, Séverine; Allegra, Marilyn; Desnuelle, Claude; Bardoni, Barbara

doi:10.1136/jmg.2008.060541

Cited by 55 publications

(60 citation statements)

References 24 publications

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“…In zebrafish, knockdown of FXR1 with antisense RNAs caused abnormalities in striated muscle and severe cardiomyopathy resulting in heart failure in embryos (Padje et al 2009). Finally, in humans, altered expression of musclespecific isoforms of FXR1P has been implicated in facioscapulohumeral muscular dystrophy (FSHD) because patients have abnormal expression patterns of three different FXR1P isoforms in myoblasts and myotubes (Davidovic et al 2008). Collectively, these studies underscore the important role of FXR1P in normal muscle development.…”

Section: Introductionmentioning

confidence: 72%

Fragile X protein family member FXR1P is regulated by microRNAs

Cheever

Blackwell

Ceman

2010

RNA

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FXR1P is one of two autosomal paralogs of the fragile X mental retardation protein FMRP. The absence of FMRP causes fragile X syndrome, the leading cause of hereditary mental retardation. FXR1P plays an important role in normal muscle development and has been implicated in facioscapulohumeral muscular dystrophy (FSHD). Its absence also causes cardiac abnormalities in both mice and zebrafish. To examine miRNA-mediated regulation of FMRP and FXR1P, we studied their expression in a conditional Dicer knockdown cell line, DT40. We found that FXR1P, but not FMRP, is significantly increased upon Dicer knockdown and the consequent reduction of miRNAs, suggesting that FXR1P is regulated by miRNAs while FMRP is not in DT40 cells. Expression of a luciferase reporter bearing the 39 untranslated region (39UTR) of FXR1 was significantly increased in the absence of miRNAs, confirming miRNA-mediated regulation of FXR1P, while a luciferase reporter bearing the FMR1 39UTR was not. We identified one of the regulatory regions in the 39UTR of FXR1 by removing a conserved, 8-nucleotide miRNA seed sequence common to miRNAs 25, 32, 92, 363, and 367 and demonstrated loss of miRNA-mediated suppression. Treatment with specific miRNA hairpin inhibitors to each of the miRNAs in the seed sequence showed that miRs 92b, 363, and 367 regulated FXR1P expression. Accordingly, overexpression of the miRNA 367 mimic significantly decreased endogenous FXR1P expression in human cell lines HEK-293T and HeLa. We report for the first time that FXR1P is regulated through miRNA binding, with one site being the miR-25/32/92/363/367 seed sequence.

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Section: Introductionmentioning

confidence: 72%

Fragile X protein family member FXR1P is regulated by microRNAs

Cheever

Blackwell

Ceman

2010

RNA

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“…At least FMR1 and FXR1 are expressed as differential isoforms, with some transcripts expressed more strongly in some tissues than others (Davidovic et al, 2008;Denman and Sung, 2002;Huang et al, 1996;Khandjian et al, 1998;Kirkpatrick et al, 1999;Sittler et al, 1996). The fact that the full-length FMR1 construct rescues all phenotypes indicates that the FMR1 transcript heterogeneity is dispensable, at least at the level of the phenotypes assayed here.…”

Section: Dmmbiologistsorg 480mentioning

confidence: 90%

Fragile X mental retardation protein has a unique, evolutionarily conserved neuronal function not shared with FXR1P or FXR2P

Coffee

Tessier

Woodruff

et al. 2010

Disease Models &Amp; Mechanisms

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SUMMARYFragile X syndrome (FXS), resulting solely from the loss of function of the human fragile X mental retardation 1 (hFMR1) gene, is the most common heritable cause of mental retardation and autism disorders, with syndromic defects also in non-neuronal tissues. In addition, the human genome encodes two closely related hFMR1 paralogs: hFXR1 and hFXR2. The Drosophila genome, by contrast, encodes a single dFMR1 gene with close sequence homology to all three human genes. Drosophila that lack the dFMR1 gene (dfmr1 null mutants) recapitulate FXS-associated molecular, cellular and behavioral phenotypes, suggesting that FMR1 function has been conserved, albeit with specific functions possibly sub-served by the expanded human gene family. To test evolutionary conservation, we used tissue-targeted transgenic expression of all three human genes in the Drosophila disease model to investigate function at (1) molecular, (2) neuronal and (3) non-neuronal levels. In neurons, dfmr1 null mutants exhibit elevated protein levels that alter the central brain and neuromuscular junction (NMJ) synaptic architecture, including an increase in synapse area, branching and bouton numbers. Importantly, hFMR1 can, comparably to dFMR1, fully rescue both the molecular and cellular defects in neurons, whereas hFXR1 and hFXR2 provide absolutely no rescue. For non-neuronal requirements, we assayed male fecundity and testes function. dfmr1 null mutants are effectively sterile owing to disruption of the 9+2 microtubule organization in the sperm tail. Importantly, all three human genes fully and equally rescue mutant fecundity and spermatogenesis defects. These results indicate that FMR1 gene function is evolutionarily conserved in neural mechanisms and cannot be compensated by either FXR1 or FXR2, but that all three proteins can substitute for each other in non-neuronal requirements. We conclude that FMR1 has a neural-specific function that is distinct from its paralogs, and that the unique FMR1 function is responsible for regulating neuronal protein expression and synaptic connectivity.Fragile X mental retardation protein has a unique, evolutionarily conserved neuronal function not shared with FXR1P or FXR2P

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“…The investigation of these possibilities is the focus of ongoing investigation. Interestingly, two recent reports described an alteration of FXR1 expression in muscle disease, indicating a role of FXR1P in the pathophysiology of these specific disorders (Davidovic et al, 2008;Orengo et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Reduction in fragile X related 1 protein causes cardiomyopathy and muscular dystrophy in zebrafish

Padje

Chaudhry

Severijnen

et al. 2009

Journal of Experimental Biology

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SUMMARYLack of the FMR1 gene product causes fragile X syndrome, the commonest inherited cause of mental impairment. We know little of the roles that fragile X related (FXR) gene family members (FMR1, FXR2 and FXR1) play during embryonic development. Although all are expressed in the brain and testis, FXR1 is the principal member found in striated and cardiac muscle. The Fxr1 knockout mice display a striated muscle phenotype but it is not known why they die shortly after birth; however, a cardiac cause is possible. The zebrafish is an ideal model to investigate the role of fxr1 during development of the heart. We have carried out morpholino knockdown of fxr1 and have demonstrated abnormalities of striated muscle development and abnormal development of the zebrafish heart, including failure of looping and snapping of the atrium from its venous pole. In addition, we have measured cardiac function using high-speed video microscopy and demonstrated a significant reduction in cardiac function. This cardiac phenotype has not been previously described and suggests that fxr1 is essential for normal cardiac form and function.Supplementary material available online at

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Alteration of expression of muscle specific isoforms of the fragile X related protein 1 (FXR1P) in facioscapulohumeral muscular dystrophy patients

Cited by 55 publications

References 24 publications

Fragile X protein family member FXR1P is regulated by microRNAs

Fragile X protein family member FXR1P is regulated by microRNAs

Fragile X mental retardation protein has a unique, evolutionarily conserved neuronal function not shared with FXR1P or FXR2P

Reduction in fragile X related 1 protein causes cardiomyopathy and muscular dystrophy in zebrafish

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