Allamand Valérie, Richard Pascale, Lescure Alain, Ledeuil Céline, Desjardin Delphine, Petit Nathalie, Gartioux Corine, Ferreiro Ana, Krol Alain, Pellegrini Nadine, Urtizberea J Andoni, Guicheney Pascale
Institut National de la Santé et de la Recherche Médicale, U582, Institut de Myologie, IFR 14, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
EMBO Rep. 2006 Apr;7(4):450-4. doi: 10.1038/sj.embor.7400648. Epub 2006 Feb 24.
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.
编码硒蛋白N（SelN）的SEPN1基因突变已在不同的先天性肌病中被描述。在此，我们报告了一名患有典型（尽管症状较轻）的刚性脊柱型肌营养不良症患者的SelN信使核糖核酸（mRNA）的硒代半胱氨酸插入序列（SECIS）中的首个突变，SECIS是位于3'非翻译区的一种发夹结构。我们在该患者的皮肤成纤维细胞中检测到mRNA和蛋白质水平均显著降低。SECIS元件通过招募SECIS结合蛋白2（SBP2），对于在重新编程的UGA密码子处插入硒代半胱氨酸至关重要，并且我们证明该突变在体外消除了SBP2与SECIS的结合，从而阻止了硒代半胱氨酸的共翻译掺入和SelN的合成。这种影响SECIS功能基序中保守碱基的突变的鉴定，从而揭示了导致SEPN1相关肌病的一种新病理机制的结构基础。
