Siuda Joanna, Jasinska-Myga Barbara, Boczarska-Jedynak Magdalena, Opala Grzegorz, Fiesel Fabienne C, Moussaud-Lamodière Elisabeth L, Scarffe Leslie A, Dawson Valina L, Ross Owen A, Springer Wolfdieter, Dawson Ted M, Wszolek Zbigniew K
Department of Neurology, Silesian Medical University, Katowice, Poland; Department of Neuroscience, Mayo Clinic Jacksonville, Florida, USA.
Department of Neurology, Silesian Medical University, Katowice, Poland.
Parkinsonism Relat Disord. 2014 Nov;20(11):1274-8. doi: 10.1016/j.parkreldis.2014.08.019. Epub 2014 Sep 2.
Recessive mutations in the PTEN-induced putative kinase 1 (PINK1) gene cause early-onset Parkinson's disease (EOPD). The clinical phenotype of families that have this PINK1-associated disease may present with different symptoms, including typical PD. The loss of the PINK1 protein may lead to mitochondrial dysfunction, which causes dopaminergic neuron death.
The clinical phenotypes of a large Polish family with EOPD and an identified PINK1 homozygous nonsense mutation were assessed. Ubiquitination and degradation of mitochondrial parkin substrates as well as mitochondrial bioenergetics were investigated as direct functional readouts for PINK1's kinase activity in biopsied dermal fibroblasts.
A four-generation family was genealogically evaluated. Genetic screening identified two affected subjects who were both homozygous carriers of the pathogenic PINK1 p.Q456X substitution. Both patients presented with dystonia and gait disorders at symptom onset. Seven heterozygous mutation carriers remained unaffected. Functional studies revealed that the PINK1 p.Q456X protein is non-functional in activating the downstream ubiquitin ligase parkin and priming the ubiquitination of its substrates, and that the RNA levels of PINK1 were significantly reduced.
The PINK1 p.Q456X mutation leads to a decrease in mRNA and a loss of protein function. The foot dystonia and gait disorders seen at disease onset in affected members of our family, which were accompanied by parkinsonism had a similar clinical presentation to what has been described in previous reports of PINK1 mutation carriers.
磷酸酶及张力蛋白同源物诱导激酶1（PINK1）基因的隐性突变会导致早发性帕金森病（EOPD）。患有这种与PINK1相关疾病的家族的临床表型可能呈现出不同症状，包括典型的帕金森病。PINK1蛋白的缺失可能导致线粒体功能障碍，进而引起多巴胺能神经元死亡。
对一个患有EOPD且已鉴定出PINK1纯合无义突变的大型波兰家族的临床表型进行评估。研究了线粒体帕金底物的泛素化和降解以及线粒体生物能量学，以此作为活检皮肤成纤维细胞中PINK1激酶活性的直接功能读数。
对一个四代家族进行了系谱评估。基因筛查确定了两名受影响的受试者，他们都是致病性PINK1 p.Q456X替代的纯合携带者。两名患者在症状发作时均出现肌张力障碍和步态障碍。七名杂合突变携带者未受影响。功能研究表明，PINK1 p.Q456X蛋白在激活下游泛素连接酶帕金和引发其底物的泛素化方面无功能，且PINK1的RNA水平显著降低。
PINK1 p.Q456X突变导致mRNA减少和蛋白质功能丧失。我们家族中受影响成员在疾病发作时出现的足部肌张力障碍和步态障碍，伴有帕金森综合征，其临床表现与先前关于PINK1突变携带者的报道中所描述的相似。
