Drug-induced readthrough of premature stop codons leads to the stabilization of laminin α2 chain mRNA in CMD myotubes

Valérie Allamand, Laure Bidou, Masayuki Arakawa, Célia Floquet, Masataka Shiozuka, Marion Paturneau-Jouas, Corine Gartioux, Gillian S. Butler-Browne, Vincent Mouly, Jean Pierre Rousset, Ryoichi Matsuda, Daishiro Ikeda, Pascale Guicheney

研究成果: ジャーナルへの寄稿学術誌査読

64 被引用数 (Scopus)


Background: The most common form of congenital muscular dystrophy is caused by a deficiency in the α2 chain of laminin-211, a protein of the extracellular matrix. A wide variety of mutations, including 20 to 30% of nonsense mutations, have been identified in the corresponding gene, LAMA2. A promising approach for the treatment of genetic disorders due to premature termination codons (PTCs) is the use of drugs to force stop codon readthrough. Methods: Here, we analyzed the effects of two compounds on a PTC in the LAMA2 gene that targets the mRNA to nonsense-mediated RNA decay, in vitro using a dual reporter assay, as well as ex vivo in patient-derived myotubes. Results: We first showed that both gentamicin and negamycin promote significant readthrough of this PTC. We then demonstrated that the mutant mRNAs were strongly stabilized in patient-derived myotubes after administration of negamycin, but not gentamicin. Nevertheless, neither treatment allowed re-expression of the laminin α2-chain protein, pointing to problems that may have arisen at the translational or post-translational levels. Conclusions: Taken together, our results emphasize that achievement of a clinical benefit upon treatment with novel readthrough-inducing agents would require several favourable conditions including PTC nucleotide context, intrinsic and induced stability of mRNA and correct synthesis of a full-length active protein.

ジャーナルJournal of Gene Medicine
出版ステータス出版済み - 2月 2008

!!!All Science Journal Classification (ASJC) codes

  • 分子医療
  • 分子生物学
  • 遺伝学
  • 創薬
  • 遺伝学(臨床)


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