SMA-causing missense mutations in survival motor neuron (Smn) display a wide range of phenotypes when modeled in Drosophila.
SMA-causing missense mutations in survival motor neuron (Smn) display a wide range of phenotypes when modeled in Drosophila.
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DOI：
10.1371/journal.pgen.1004489
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发表时间：
2014-08
期刊：
影响因子：
4.5
通讯作者：
Matera AG
中科院分区：
文献类型：
--
作者：
Praveen K;Wen Y;Gray KM;Noto JJ;Patlolla AR;Van Duyne GD;Matera AG
人类生存运动神经元1 （SMN）基因突变是脊髓性肌萎缩症（SMA）的主要原因，这是一种毁灭性的神经肌肉疾病。SMN蛋白在剪接体的核心成分小核核糖核蛋白（snRNPs）的生物发生中具有很好的作用。其他组织特异性和全局功能被归因于SMN；然而，它们与SMA病理的相关性尚不清楚且存在争议。使用果蝇作为模型系统，我们创建了12个Smn错义突变的等位基因系列，最初在人类SMA患者中发现。我们发现，表达这些sma引起的突变的动物表现出广泛的表型严重程度，与人类疾病相似。此外，已知SMN在RNP组装中与其他蛋白质的特定相互作用对于SMN的作用是重要的，这是保守的。基因内互补分析显示，三个最严重的突变都位于SMN的YG盒自寡聚化结构域，表现出比空等位基因更强的表型，并表现出显性方式。为了支持这一发现，严重的YG盒突变体在自相互作用试验中存在缺陷，但仍保持其与野生型SMN异二聚化的能力。当高水平表达时，野生型SMN能够抑制突变蛋白的活性。这些结果表明，某些SMN突变体可以将野生型蛋白隔离到无活性复合物中。SMN YG盒二聚体的分子模型为这种显性表型提供了结构基础。这些数据表明，SMN YG盒的重要结构和功能特征在脊椎动物和无脊椎动物之间是保守的，强调了自相互作用对SMN正常功能的重要性。脊髓性肌萎缩症（SMA）是一种常见的儿童神经肌肉疾病，最常见的形式是在两岁之前导致死亡。每50个美国人中就有一个是SMA的携带者，这使得这种遗传疾病成为一个严重的健康问题。SMA是由存活运动神经元1 （SMN1）基因的功能突变丧失引起的。SMN是一种必需蛋白，在小核核糖核蛋白（snRNPs）的组装中具有很好的功能，snRNPs是剪接体的核心成分。为了阐明破坏特定SMN蛋白相互作用的表型后果，我们以黑腹果蝇为模型，生成了一系列引起sma的点突变。使用这个系统，我们已经证明SMN结构和功能的关键方面在人类和苍蝇之间是保守的。基因内互补分析揭示了野生型和突变型SMN亚基之间潜在的显性负相互作用，强调了YG盒在形成高阶SMN多聚体中的本质。这些结果为未来研究针对恢复功能性SMN低聚物的治疗提供了基础。
Mutations in the human survival motor neuron 1 (SMN) gene are the primary cause of spinal muscular atrophy (SMA), a devastating neuromuscular disorder. SMN protein has a well-characterized role in the biogenesis of small nuclear ribonucleoproteins (snRNPs), core components of the spliceosome. Additional tissue-specific and global functions have been ascribed to SMN; however, their relevance to SMA pathology is poorly understood and controversial. Using Drosophila as a model system, we created an allelic series of twelve Smn missense mutations, originally identified in human SMA patients. We show that animals expressing these SMA-causing mutations display a broad range of phenotypic severities, similar to the human disease. Furthermore, specific interactions with other proteins known to be important for SMN's role in RNP assembly are conserved. Intragenic complementation analyses revealed that the three most severe mutations, all of which map to the YG box self-oligomerization domain of SMN, display a stronger phenotype than the null allele and behave in a dominant fashion. In support of this finding, the severe YG box mutants are defective in self-interaction assays, yet maintain their ability to heterodimerize with wild-type SMN. When expressed at high levels, wild-type SMN is able to suppress the activity of the mutant protein. These results suggest that certain SMN mutants can sequester the wild-type protein into inactive complexes. Molecular modeling of the SMN YG box dimer provides a structural basis for this dominant phenotype. These data demonstrate that important structural and functional features of the SMN YG box are conserved between vertebrates and invertebrates, emphasizing the importance of self-interaction to the proper functioning of SMN. Spinal Muscular Atrophy (SMA) is a prevalent childhood neuromuscular disease, which in its most common form causes death by the age of two. One in fifty Americans is a carrier for SMA, making this genetic disease a serious health concern. SMA is caused by loss of function mutations in the survival motor neuron 1 (SMN1) gene. SMN is an essential protein and has a well-characterized function in the assembly of small nuclear ribonucleoproteins (snRNPs), which are core components of the spliceosome. To elucidate the phenotypic consequences of disrupting specific SMN protein interactions, we have generated a series of SMA-causing point mutations, modeled in Drosophila melanogaster. Using this system, we have shown that key aspects of SMN structure and function are conserved between humans and flies. Intragenic complementation analyses reveal the potential for dominant negative interactions between wild-type and mutant SMN subunits, highlighting the essential nature of the YG box in formation of higher-order SMN multimers. These results provide a basis for future studies investigating therapy targeted at restoration of functional SMN oligomers.
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影响因子：
4.9
作者：
Boyer, Justin G.;Murray, Lyndsay M.;Kothary, Rashmi
通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
4.5
作者：
Gonsalvez, Graydon B.;Praveen, Kavita;Matera, A. Gregory
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影响因子：
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作者：
Gonsalvez, Graydon B.;Rajendra, T. K.;Matera, A. Gregory
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SMN是果蝇中感觉运动电路函数所必需的。
影响因子：
64.5
作者：
Imlach WL;Beck ES;Choi BJ;Lotti F;Pellizzoni L;McCabe BD
通讯作者：
McCabe BD