A single homozygous point mutation in a 3′ untranslated region motif of selenoprotein N mRNA causes SEPN1-related myopathy
A single homozygous point mutation in a 3′ untranslated region motif of selenoprotein N mRNA causes SEPN1-related myopathy
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DOI：
10.1038/sj.embor.7400648
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发表时间：
2006-04-01
期刊：
影响因子：
7.7
通讯作者：
Guicheney, P
中科院分区：
文献类型：
--
作者：
Allamand, V;Richard, P;Guicheney, P
编码硒蛋白N（SelN）的SEPN1基因的突变已在不同的先天性肌病中描述。在这里，我们报告的第一个突变的硒代半胱氨酸插入序列（SECIS）的SelN信使RNA，位于30非翻译区的发夹结构，在一个典型的，但轻度形式的刚性脊柱肌营养不良症的患者。我们检测到患者皮肤成纤维细胞的mRNA和蛋白质水平均显著降低。SECIS元件对于通过募集SECIS结合蛋白2（SBP2）在重编程的UGA密码子处插入硒代半胱氨酸是至关重要的，并且我们证明了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和SelN合成的共翻译掺入。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相关肌病的新病理机制的结构基础。
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 30 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.