The hereditary spastic paraplegias (HSP) are among the most genetically diverse of all Mendelian disorders. They comprise a large group of neurodegenerative diseases that may be divided into 'pure HSP' in forms of the disease primarily entailing progressive lower-limb weakness and spasticity, and 'complex HSP' when these features are accompanied by other neurological (or non-neurological) clinical signs. Here, we identified biallelic variants in the transmembrane protein 63C (TMEM63C) gene, encoding a predicted osmosensitive calcium-permeable cation channel, in individuals with hereditary spastic paraplegias associated with mild intellectual disability in some, but not all cases. Biochemical and microscopy analyses revealed that TMEM63C is an endoplasmic reticulum-localized protein, which is particularly enriched at mitochondria-endoplasmic reticulum contact sites. Functional in cellula studies indicate a role for TMEM63C in regulating both endoplasmic reticulum and mitochondrial morphologies. Together, these findings identify autosomal recessive TMEM63C variants as a cause of pure and complex HSP and add to the growing evidence of a fundamental pathomolecular role of perturbed mitochondrial-endoplasmic reticulum dynamics in motor neurone degenerative diseases.

中文翻译：

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TMEM63C 突变导致线粒体形态学缺陷并成为遗传性痉挛性截瘫的基础。

遗传性痉挛性截瘫 (HSP) 是所有孟德尔疾病中最具遗传多样性的疾病之一。它们包括一大类神经退行性疾病，可分为主要表现为进行性下肢无力和痉挛的“纯 HSP”和当这些特征伴有其他神经（或非神经）疾病时的“复杂 HSP” ) 临床症状。在这里，我们鉴定了跨膜蛋白 63C (TMEM63C) 基因的双等位基因变异，该基因编码预测的渗透敏感的钙渗透阳离子通道，在某些但不是所有病例中与轻度智力障碍相关的遗传性痉挛性截瘫患者中。生化和显微镜分析表明，TMEM63C 是一种内质网定位蛋白，尤其在线粒体-内质网接触部位富集。细胞功能研究表明 TMEM63C 在调节内质网和线粒体形态方面的作用。总之，这些发现将常染色体隐性遗传 TMEM63C 变异确定为纯和复杂 HSP 的原因，并增加了越来越多的证据表明扰动的线粒体 - 内质网动力学在运动神经元退行性疾病中的基本病理分子作用。