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A single homozygous point mutation in a 3′untranslated region motif of selenoprotein N mRNA causes SEPN1‐related myopathy

2006; Springer Nature; Volume: 7; Issue: 4 Linguagem: Inglês

10.1038/sj.embor.7400648

1469-3178

Valérie Allamand, Pascale Richard, Alain Lescure, C. Ledeuil, Delphine Desjardin, Nathalie Petit, Corine Gartioux, Ana Ferreiro, Alain Krol, N. Pellegrini, Jon Andoni Urtizberea, Pascale Guicheney,

Porphyrin Metabolism and Disorders

Mutations in the SEPN1 gene encoding the selenoprotein N (SelN) have been described in different congenital myopathies. Here, we report the first mutation in the selenocysteine insertion sequence (SECIS) of SelN messenger RNA, a hairpin structure located in the 3' untranslated region, in a patient presenting a classical although mild form of rigid spine muscular dystrophy. We detected a significant reduction in both mRNA and protein levels in the patient's skin fibroblasts. The SECIS element is crucial for the insertion of selenocysteine at the reprogrammed UGA codon by recruiting the SECIS-binding protein 2 (SBP2), and we demonstrated that this mutation abolishes SBP2 binding to SECIS in vitro, thereby preventing co-translational incorporation of selenocysteine and SelN synthesis. The identification of this mutation affecting a conserved base in the SECIS functional motif thereby reveals the structural basis for a novel pathological mechanism leading to SEPN1-related myopathy.