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Haack, T.B. ; Ignatius, E.* ; Calvo-Garrido, J.* ; Iuso, A. ; Isohanni, P.* ; Maffezzini, C.* ; Lönnqvist, T.* ; Suomalainen, A.* ; Gorza, M. ; Kremer, L.S. ; Graf, E. ; Hartig, M.* ; Berutti, R. ; Paucar, M.* ; Svenningsson, P.* ; Stranneheim, H.* ; Brandberg, G.* ; Wedell, A.* ; Kurian, M.A.* ; Hayflick, S.A.* ; Venco, P.* ; Tiranti, V.* ; Strom, T.M. ; Dichgans, M.* ; Horvath, R.* ; Holinski-Feder, E.* ; Freyer, C.* ; Meitinger, T. ; Prokisch, H. ; Senderek, J.* ; Wredenberg, A.* ; Carroll, C.J.* ; Klopstock, T.*

Absence of the autophagy adaptor SQSTM1/p62 causes childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy.

Am. J. Hum. Genet. 99, 735-743 (2016)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords P62/sqstm1; Mutations; Mitophagy; Parkin; P62; Mitochondria; Protein; Receptors; Disease; Cancer
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Journal American Journal of Human Genetics, The
Quellenangaben Volume: 99, Issue: 3, Pages: 735-743 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)
Institute of Diabetes and Obesity (IDO)