Haack Tobias B, Ignatius Erika, Calvo-Garrido Javier, Iuso Arcangela, Isohanni Pirjo, Maffezzini Camilla, Lönnqvist Tuula, Suomalainen Anu, Gorza Matteo, Kremer Laura S, Graf Elisabeth, Hartig Monika, Berutti Riccardo, Paucar Martin, Svenningsson Per, Stranneheim Henrik, Brandberg Göran, Wedell Anna, Kurian Manju A, Hayflick Susan A, Venco Paola, Tiranti Valeria, Strom Tim M, Dichgans Martin, Horvath Rita, Holinski-Feder Elke, Freyer Christoph, Meitinger Thomas, Prokisch Holger, Senderek Jan, Wredenberg Anna, Carroll Christopher J, Klopstock Thomas
Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland; Department of Child Neurology, Children's Hospital, University of Helsinki and Helsinki University Hospital, 00029 HUS, Finland.
Am J Hum Genet. 2016 Sep 1;99(3):735-743. doi: 10.1016/j.ajhg.2016.06.026. Epub 2016 Aug 18.
SQSTM1 (sequestosome 1; also known as p62) encodes a multidomain scaffolding protein involved in various key cellular processes, including the removal of damaged mitochondria by its function as a selective autophagy receptor. Heterozygous variants in SQSTM1 have been associated with Paget disease of the bone and might contribute to neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Using exome sequencing, we identified three different biallelic loss-of-function variants in SQSTM1 in nine affected individuals from four families with a childhood- or adolescence-onset neurodegenerative disorder characterized by gait abnormalities, ataxia, dysarthria, dystonia, vertical gaze palsy, and cognitive decline. We confirmed absence of the SQSTM1/p62 protein in affected individuals' fibroblasts and found evidence of a defect in the early response to mitochondrial depolarization and autophagosome formation. Our findings expand the SQSTM1-associated phenotypic spectrum and lend further support to the concept of disturbed selective autophagy pathways in neurodegenerative diseases.
SQSTM1（sequestosome 1；也称为p62）编码一种多结构域支架蛋白，参与各种关键的细胞过程，包括通过作为选择性自噬受体的功能清除受损线粒体。SQSTM1中的杂合变异与骨Paget病相关，可能在肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）的神经退行性变中起作用。通过外显子组测序，我们在来自四个家庭的九名受影响个体中鉴定出SQSTM1中的三种不同的双等位基因功能丧失变异，这些个体患有以步态异常、共济失调、构音障碍、肌张力障碍、垂直凝视麻痹和认知衰退为特征的儿童期或青少年期发病的神经退行性疾病。我们证实受影响个体的成纤维细胞中不存在SQSTM1/p62蛋白，并发现线粒体去极化和自噬体形成早期反应存在缺陷的证据。我们的研究结果扩展了与SQSTM1相关的表型谱，并进一步支持神经退行性疾病中选择性自噬途径紊乱的概念。
