Wang Bin, Wei Bin, Lu Likui, Liu Sha, Ge Wei, Sun Miao
Department of Fetology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, China.
Neurogenetics. 2025 May 26;26(1):45. doi: 10.1007/s10048-025-00827-6.
Essential tremor (ET) is a common movement disorder, but its pathophysiologic mechanisms remain elusive. So far, a few genes/loci have been identified, but because of genetic heterogeneity, the genetic etiology of ET is still one of the main challenges. In this study, we report an autosomal dominant ET Chinese pedigree in which the patients presented with involuntary tremor of the head or upper limbs, with a slow progression of symptoms, no difficulty in starting and turning, no slow walking, no other significant findings were noted on neurological examination. A heterozygous missense mutation (c.158G > A, p.G53D) in PINK1 (PTEN-induced kinase 1) was identified by whole-exome sequencing of four affected individuals from this ET family. Confirmed by Sanger sequencing, we find that this PINK1 missense variant co-segregate with ET phenotypes in this pedigree with all the affected subjects, showing clear genotype-phenotype correlation. In addition, the new missense mutation was functionally analyzed by western blotting and mitochondrial membrane potential assay after cell transfection. It was found that PINK1 may play a protective role for cells, whereas the c.158G > A (p.G53D) missense mutation leads to a loss of cellular protection, thereby increasing cellular sensitivity to stress. Thus, this study provides a heterozygous missense mutation in PINK1 potentially associated with ET.
特发性震颤（ET）是一种常见的运动障碍，但其病理生理机制仍不清楚。到目前为止，已经鉴定出一些基因/基因座，但由于遗传异质性，ET的遗传病因仍然是主要挑战之一。在本研究中，我们报告了一个常染色体显性遗传的ET中国家系，其中患者表现为头部或上肢的不自主震颤，症状进展缓慢，起始和转身无困难，行走不缓慢，神经系统检查未发现其他明显异常。通过对这个ET家系的四名患病个体进行全外显子组测序，在PTEN诱导激酶1（PINK1）中鉴定出一个杂合错义突变（c.158G＞A，p.G53D）。经Sanger测序证实，我们发现这个PINK1错义变体在这个家系中与所有患病个体的ET表型共分离，显示出明确的基因型-表型相关性。此外，通过细胞转染后的蛋白质印迹和线粒体膜电位测定对新的错义突变进行了功能分析。发现PINK1可能对细胞起保护作用，而c.158G＞A（p.G53D）错义突变导致细胞保护作用丧失，从而增加细胞对应激的敏感性。因此，本研究提供了一个可能与ET相关的PINK1杂合错义突变。
