Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, India.
Mov Disord. 2024 Jul;39(7):1217-1225. doi: 10.1002/mds.29792. Epub 2024 Apr 8.
Most Parkinson's disease (PD) loci have shown low prevalence in the Indian population, highlighting the need for further research.
The aim of this study was to characterize a novel phosphatase tensin homolog-induced serine/threonine kinase 1 (PINK1) mutation causing PD in an Indian family.
Exome sequencing of a well-characterized Indian family with PD. A novel PINK1 mutation was studied by in silico modeling using AlphaFold2, expression of mutant PINK1 in human cells depleted of functional endogenous PINK1, followed by quantitative image analysis and biochemical assessment.
We identified a homozygous chr1:20648535-20648535 T>C on GRCh38 (p.F385S) mutation in exon 6 of PINK1, which was absent in 1029 genomes from India and in other known databases. PINK1 F385S lies within the highly conserved DFG motif, destabilizes its active state, and impairs phosphorylation of ubiquitin at serine 65 and proper engagement of parkin upon mitochondrial depolarization.
We characterized a novel nonconservative mutation in the DFG motif of PINK1, which causes loss of its ubiquitin kinase activity and inhibition of mitophagy. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
大多数帕金森病（PD）基因座在印度人群中的患病率较低，这凸显了进一步研究的必要性。
本研究旨在描述一个新的磷酸酶张力蛋白同源物诱导丝氨酸/苏氨酸激酶 1（PINK1）突变，该突变导致一个印度家族发生 PD。
对一个具有 PD 特征的印度家族进行外显子组测序。使用 AlphaFold2 对新发现的 PINK1 突变进行计算机模拟，在功能性内源性 PINK1 耗尽的人类细胞中表达突变型 PINK1，然后进行定量图像分析和生化评估。
我们在 GRCh38 上鉴定出 PINK1 基因第 6 外显子中的一个纯合 chr1:20648535-20648535T>C 突变（p.F385S），该突变在来自印度的 1029 个人类基因组和其他已知数据库中均不存在。PINK1 F385S 位于高度保守的 DFG 基序内，使其不稳定处于活性状态，并损害了泛素在丝氨酸 65 位的磷酸化以及在线粒体去极化时 parkin 的正确结合。
我们描述了 PINK1 DFG 基序中的一个新的非保守突变，该突变导致其泛素激酶活性丧失和线粒体自噬抑制。
