SAM68 is a physiological regulator of SMN2 splicing in spinal muscular atrophy

Vittoria Pagliarini, Laura Pelosi, Maria Blaire Bustamante, Annalisa Nobili, Maria Grazia Berardinelli, Marcello D'Amelio, Antonio Musarò, Claudio Sette

Risultato della ricerca: Contributo in rivistaArticolo in rivista

20 Citazioni (Scopus)


Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by loss of motor neurons in patients with null mutations in the SMN1 gene. The almost identical SMN2 gene is unable to compensate for this deficiency because of the skipping of exon 7 during pre-messenger RNA (mRNA) processing. Although several splicing factors can modulate SMN2 splicing in vitro, the physiological regulators of this disease-causing event are unknown. We found that knockout of the splicing factor SAM68 partially rescued body weight and viability of SMA?7 mice. Ablation of SAM68 function promoted SMN2 splicing and expression in SMA?7 mice, correlating with amelioration of SMA-related defects in motor neurons and skeletal muscles. Mechanistically, SAM68 binds to SMN2 pre-mRNA, favoring recruitment of the splicing repressor hnRNP A1 and interfering with that of U2AF65 at the 3' splice site of exon 7. These findings identify SAM68 as the first physiological regulator of SMN2 splicing in an SMA mouse model.
Lingua originaleEnglish
pagine (da-a)77-90
Numero di pagine14
Stato di pubblicazionePubblicato - 2015


  • Adaptor Proteins, Signal Transducing
  • Animals
  • Base Sequence
  • Cell Biology
  • Female
  • HEK293 Cells
  • Heterogeneous Nuclear Ribonucleoprotein A1
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • Motor Neurons
  • Muscular Atrophy, Spinal
  • RNA Splicing
  • RNA-Binding Proteins
  • Spinal Cord
  • Survival of Motor Neuron 2 Protein


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