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

• Published in: American journal of human genetics Vol. 99; no. 3; pp. 735 - 743
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2016; Cell Press; Elsevier
• Subjects: Adolescent; Adult; Age of Onset; Amyotrophic lateral sclerosis; Ataxia - complications; Ataxia - genetics; Autophagosomes - metabolism; Autophagosomes - pathology; Autophagy; Autophagy - genetics; Child; Cognition Disorders - genetics; Dementia; Dysarthria - complications; Dysarthria - genetics; Dystonia - complications; Dystonia - genetics; Female; Fibroblasts - metabolism; Gait - genetics; Genotype & phenotype; Humans; Male; Medicin och hälsovetenskap; Mitochondria; Mitochondria - metabolism; Mitochondria - pathology; Movement Disorders - complications; Movement Disorders - genetics; Neurodegenerative Diseases - complications; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - physiopathology; Pedigree; Phenotype; Proteins; RNA, Messenger - analysis; Sequestosome-1 Protein - deficiency; Sequestosome-1 Protein - genetics; Supranuclear Palsy, Progressive - complications; Supranuclear Palsy, Progressive - genetics; Young Adult
• ISSN: 0002-9297; 1537-6605; 1537-6605
• 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 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.