Department of Medical and Surgical Sciences (DIMEC), St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
Department of Pharmacy and Biotechnology (FaBit), University of Bologna, Bologna, Italy.
FASEB J. 2019 Oct;33(10):11284-11302. doi: 10.1096/fj.201802722R. Epub 2019 Aug 7.
Loss-of-function mutations in the gene cause Troyer syndrome, a recessive form of spastic paraplegia resulting in muscle weakness, short stature, and cognitive defects. encodes for Spartin, a protein linked to endosomal trafficking and mitochondrial membrane potential maintenance. Here, we identified with whole exome sequencing (WES) a novel frameshift mutation in the gene in 2 brothers presenting an uncharacterized developmental delay and short stature. Functional characterization in an SH-SY5Y cell model shows that this mutation is associated with increased neurite outgrowth. These cells also show a marked decrease in mitochondrial complex I (NADH dehydrogenase) activity, coupled to decreased ATP synthesis and defective mitochondrial membrane potential. The cells also presented an increase in reactive oxygen species, extracellular pyruvate, and NADH levels, consistent with impaired complex I activity. In concordance with a severe mitochondrial failure, Spartin loss also led to an altered intracellular Ca homeostasis that was restored after transient expression of wild-type Spartin. Our data provide for the first time a thorough assessment of Spartin loss effects, including impaired complex I activity coupled to increased extracellular pyruvate. In summary, through a WES study we assign a diagnosis of Troyer syndrome to otherwise undiagnosed patients, and by functional characterization we show that the novel mutation in leads to a profound bioenergetic imbalance.-Diquigiovanni, C., Bergamini, C., Diaz, R., Liparulo, I., Bianco, F., Masin, L., Baldassarro, V. A., Rizzardi, N., Tranchina, A., Buscherini, F., Wischmeijer, A., Pippucci, T., Scarano, E., Cordelli, D. M., Fato, R., Seri, M., Paracchini, S., Bonora, E. A novel mutation in gene causes a severe neurodevelopmental delay due to mitochondrial dysfunction with complex I impairments and altered pyruvate metabolism.
基因中的功能丧失突变导致 Troyer 综合征，这是一种常染色体隐性痉挛性截瘫，导致肌肉无力、身材矮小和认知缺陷。该基因编码 Spartin，一种与内体运输和线粒体膜电位维持相关的蛋白质。在这里，我们通过全外显子组测序 (WES) 在 2 个兄弟中鉴定出一个新的 基因移码突变，他们表现出未特征化的发育迟缓及身材矮小。在 SH-SY5Y 细胞模型中的功能特征表明，该突变与神经突生长增加有关。这些细胞还显示出线粒体复合物 I（NADH 脱氢酶）活性显著降低，伴随着 ATP 合成减少和线粒体膜电位缺陷。这些细胞还表现出活性氧增加、细胞外丙酮酸和 NADH 水平升高，这与复合物 I 活性受损一致。与严重的线粒体衰竭一致，Spartin 的缺失也导致细胞内 Ca 稳态失衡，在瞬时表达野生型 Spartin 后得到恢复。我们的数据首次全面评估了 Spartin 缺失的影响，包括复合物 I 活性降低和细胞外丙酮酸增加。总之，通过 WES 研究，我们对未诊断的患者进行了 Troyer 综合征的诊断，并通过功能特征表明， 中的新突变导致严重的生物能量失衡。
