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

Tobias B B. Haack, Arcangela Iuso, Laura S S. Kremer, Monika Hartig, Tim M M. Strom, Thomas Meitinger, Holger Prokisch, Matteo Gorza, Elisabeth Graf, Riccardo Berutti, Erika Ignatius, Pirjo Isohanni, Anu Suomalainen, Christopher J J. Carroll, Tuula Lönnqvist, Javier Calvo-Garrido, Henrik Stranneheim, Anna Wedell, Camilla Maffezzini, Christoph FreyerAnna Wredenberg, Martin Paucar, Per Svenningsson, Göran Brandberg, Manju A A. Kurian, Susan A A. Hayflick, Susan A A. Hayflick, Paola Venco, Valeria Tiranti, Martin Dichgans, Thomas Klopstock, Rita Horvath, Elke Holinski-Feder, Jan Senderek

Research output: Contribution to journalArticlepeer-review

70 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)735-743
Number of pages9
JournalAmerican Journal of Human Genetics
Issue number3
StatePublished - Sep 1 2016

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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