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首页> 外文期刊>Chinese science bulletin >Genetic and structural analyses suggest that a novel SPG3A mutation causes severe phenotypes of hereditary spastic paraplegia
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Genetic and structural analyses suggest that a novel SPG3A mutation causes severe phenotypes of hereditary spastic paraplegia

机译：遗传和结构分析表明，新的SPG3A突变会导致遗传性痉挛性截瘫的严重表型

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摘要

Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases. The genotypes and phenotypes of HSP are extremely heterogenous. SPG3A is one of the identified genes underlying HSP, and codes for a GTPase, atlastin. Mutations in SPG3A are currently believed to be associated with early onset and mild phenotypes. And most structural predictions could not detect gross changes in the mutant protein. However, in a severely affected HSP family we have identified a novel SPG3A mutation, c.1228G>A (p.G410R), in a Tibetan kindred. The mutation occurred at the highly conserved nucleotide and co-segregated with the disease, and was absent in the control subjects. Structural predictions showed that the Tibetan mutation occurred at the linking part between the guanylate-binding protein domain (GB, the ball region) and the transmembrane helices (TM, the rod region) at the start point of an a-helix, which may disrupt the helix, and cause changes in the overall structure of the transmembrane region of the molecule. Our results indicate that severe phenotypes can also arise from SPG3A mutations and the linking part of the guanylate-binding protein domain and the transmembrane helices might be crucial in determining the severity of the disease. This paper not only presents the first SPG3A mutational report from the Chinese population, but also provides potential evidence for a possible correlation between the severity of the phenotypes of HSP with the extension of the changes in the protein structures of atlastin.
机译：遗传性痉挛性截瘫（HSP）是一组神经退行性疾病。 HSP的基因型和表型非常异质。 SPG3A是已鉴定的HSP基础基因之一，并编码GTPase atlastin。目前认为SPG3A中的突变与早期发作和轻度表型有关。而且大多数结构预测都无法检测到突变蛋白的总体变化。但是，在一个受严重影响的HSP家族中，我们在藏族中鉴定出一个新的SPG3A突变，即c.1228G> A（p.G410R）。突变发生在高度保守的核苷酸处，并与疾病共隔离，而在对照受试者中则不存在。结构预测表明，藏族突变发生在鸟苷酸结合蛋白结构域（GB，球形区域）和跨膜螺旋（TM，杆状区域）之间的连接部分，起始位置可能是a螺旋。螺旋，并导致分子跨膜区域的整体结构发生变化。我们的结果表明，严重的表型也可能源于SPG3A突变，鸟苷酸结合蛋白结构域和跨膜螺旋的连接部分可能对确定疾病的严重程度至关重要。本文不仅提供了来自中国人群的第一份SPG3A突变报告，而且还提供了潜在的证据证明HSP表型的严重性与atlastin蛋白质结构变化的扩展之间可能存在相关性。

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