Novel Genetic, Clinical, and Pathomechanistic Insights into TFG-Associated Hereditary Spastic Paraplegia
Novel Genetic, Clinical, and Pathomechanistic Insights into TFG-Associated Hereditary Spastic Paraplegia
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DOI：
10.1002/humu.23060
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发表时间：
2016-11-01
期刊：
影响因子：
3.9
通讯作者：
Crosby, Andrew H.
中科院分区：
文献类型：
--
作者：
Harlalka, Gaurav V.;McEntagart, Meriel E.;Crosby, Andrew H.
遗传性痉挛性截瘫 (HSP) 是一种遗传和临床异质性轴突病，主要影响上运动神经元，并且以复杂的形式影响其他神经元。在这里，我们报告了两个在 TFG 中具有明显隐性突变的家族，之前根据一个具有复杂 HSP 的小家族的发现，认为这两个家族会导致 HSP。第一个携带纯合 c.317G>A (p.R106H) 变体并呈现纯 HSP。第二个携带先前报道的相同纯合 c.316C>T (p.R106C) 变体，并表现出类似的复杂表型，包括视神经萎缩。单倍型分析和硫酸氢盐测序揭示了 c.316C>T 创始人等位基因以及 c.316_317 突变热点的证据。培养神经元中突变 TFG 蛋白的表达揭示了线粒体断裂，其程度与临床严重程度相关。我们的研究结果证实了 HSP 双等位基因 TFG 突变的因果性质，拓宽了临床和突变谱，并表明线粒体损伤代表了与其他神经退行性疾病的病理机制联系。
Hereditary spastic paraplegias (HSPs) are genetically and clinically heterogeneous axonopathies primarily affecting upper motor neurons and, in complex forms, additional neurons. Here, we report two families with distinct recessive mutations in TFG, previously suggested to cause HSP based on findings in a single small family with complex HSP. The first carried a homozygous c.317G>A (p.R106H) variant and presented with pure HSP. The second carried the same homozygous c.316C>T (p.R106C) variant previously reported and displayed a similarly complex phenotype including optic atrophy. Haplotyping and bisulfate sequencing revealed evidence for a c.316C>T founder allele, as well as for a c.316_317 mutation hotspot. Expression of mutant TFG proteins in cultured neurons revealed mitochondrial fragmentation, the extent of which correlated with clinical severity. Our findings confirm the causal nature of bi-allelic TFG mutations for HSP, broaden the clinical and mutational spectra, and suggest mitochondrial impairment to represent a pathomechanistic link to other neurodegenerative conditions.