PDF(Pubmed)
Abstract：
The SPG7 gene encodes the paraplegin protein, an inner mitochondrial membrane-localized protease. It was initially linked to pure and complicated hereditary spastic paraplegia with cerebellar atrophy, and now represents a frequent cause of undiagnosed cerebellar ataxia and spastic ataxia. We hereby report the molecular characterization and the clinical features of a large Cypriot family with five affected individuals presenting with spastic ataxia in an autosomal recessive transmission mode, due to a novel SPG7 homozygous missense variant. Detailed clinical histories of the patients were obtained, followed by neurological and neurophysiological examinations. Whole exome sequencing (WES) of the proband, in silico gene panel analysis, variant filtering and family segregation analysis of the candidate variants with Sanger sequencing were performed. RNA and protein expression as well as in vitro protein localization studies and mitochondria morphology evaluation were carried out towards functional characterization of the identified variant. The patients presented with typical spastic ataxia features while some intrafamilial phenotypic variation was noted. WES analysis revealed a novel homozygous missense variant in the SPG7 gene (c.1763C > T, p. Thr588Met), characterized as pathogenic by more than 20 in silico prediction tools. Functional studies showed that the variant does not affect neither the RNA or protein expression, nor the protein localization. However, aberrant mitochondrial morphology has been observed thus indicating mitochondrial dysfunction and further demonstrating the pathogenicity of the identified variant. Our study is the first report of an SPG7 pathogenic variant in the Cypriot population and broadens the spectrum of SPG7 pathogenic variants.
摘要：
SPG7基因编码截瘫蛋白，一种位于线粒体膜内部的蛋白酶.它最初与单纯和复杂的遗传性痉挛性截瘫伴小脑萎缩有关，现在是未诊断的小脑共济失调和痉挛性共济失调的常见原因。我们在此报告一个大型塞浦路斯家庭的分子特征和临床特征，该家庭有五个受影响的个体以常染色体隐性传播方式表现出痉挛性共济失调，由于一个新的SPG7纯合错义变体。获得了患者的详细临床病史，其次是神经和神经生理学检查。先证者的全外显子组测序（WES），计算机基因面板分析，使用Sanger测序对候选变体进行变体过滤和家族分离分析.RNA和蛋白质表达以及体外蛋白质定位研究和线粒体形态评估针对鉴定的变体的功能表征进行。患者表现出典型的痉挛性共济失调特征，同时注意到一些家族内表型变异。WES分析揭示了SPG7基因中的一个新的纯合错义变体（c.1763C>T，p.Thr588Met），被20多种计算机预测工具表征为致病性。功能研究表明，该变体不会影响RNA或蛋白质的表达，也不是蛋白质的定位。然而,已观察到异常的线粒体形态，因此表明线粒体功能障碍，并进一步证明了鉴定的变体的致病性。我们的研究是塞浦路斯人群中SPG7致病性变异的首次报道，并扩大了SPG7致病性变异的范围。
