Altered mitochondrial function in cells carrying a premutation or unmethylated full mutation of the FMR1 gene

Veronica Nobile, Federica Palumbo, Stella Lanni, Valentina Ghisio, Alberto Vitali, Massimo Castagnola, Valeria Marzano, Giuseppe Maulucci, Claudio De Angelis, Marco De Spirito, Laura Pacini, Laura D’Andrea, Gianpaolo D'Andrea, Rino Ragno, Giulia Stazi, Sergio Valente, Antonello Mai, Pietro Chiurazzi, Maurizio Genuardi, Giovanni NeriElisabetta Tabolacci

Risultato della ricerca: Contributo in rivistaArticolo in rivista

7 Citazioni (Scopus)


Fragile X-related disorders are due to a dynamic mutation of the CGG repeat at the 5′ UTR of the FMR1 gene, coding for the RNA-binding protein FMRP. As the CGG sequence expands from premutation (PM, 56-200 CGGs) to full mutation (> 200 CGGs), FMRP synthesis decreases until it is practically abolished in fragile X syndrome (FXS) patients, mainly due to FMR1 methylation. Cells from rare individuals with no intellectual disability and carriers of an unmethylated full mutation (UFM) produce slightly elevated levels of FMR1-mRNA and relatively low levels of FMRP, like in PM carriers. With the aim of clarifying how UFM cells differ from CTRL and FXS cells, a comparative proteomic approach was undertaken, from which emerged an overexpression of SOD2 in UFM cells, also confirmed in PM but not in FXS. The SOD2-mRNA bound to FMRP in UFM more than in the other cell types. The high SOD2 levels in UFM and PM cells correlated with lower levels of superoxide and reactive oxygen species (ROS), and with morphological anomalies and depolarization of the mitochondrial membrane detected through confocal microscopy. The same effect was observed in CTRL and FXS after treatment with MC2791, causing SOD2 overexpression. These mitochondrial phenotypes reverted after knock-down with siRNA against SOD2-mRNA and FMR1-mRNA in UFM and PM. Overall, these data suggest that in PM and UFM carriers, which have high levels of FMR1 transcription and may develop FXTAS, SOD2 overexpression helps to maintain low levels of both superoxide and ROS with signs of mitochondrial degradation.
Lingua originaleEnglish
pagine (da-a)227-245
Numero di pagine19
RivistaHuman Genetics
Stato di pubblicazionePubblicato - 2020


  • fragile X syndrome
  • mitochondrial anomalies


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