Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy

作者：Haack Tobias B^*; Ignatius Erika; Calvo Garrido Javier; Iuso Arcangela; Isohanni Pirjo; Maffezzini Camilla; Lonnqvist Tuula; Suomalainen Anu; Gorza Matteo; Kremer Laura S; Graf Elisabeth; Hartig Monika; Berutti Riccardo; Paucar Martin; Svenningsson Per; Stranneheim Henrik; Brandberg Goran; 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

来源：American Journal of Human Genetics, 2016, 99(3): 735-743.

DOI：10.1016/j.ajhg.2016.06.026

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 SQSTMI 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 SQSTMI 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 SQSTMl/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 SQSTMI-associated phenotypic spectrum and lend further support to the concept of disturbed selective autophagy pathways in neurodegenerative diseases.

• 出版日期2016-9-1