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

Haack, TB; Ignatius, E; Calvo-Garrido, J; Iuso, A; Isohanni, P; Maffezzini, C; Lönnqvist, T; Suomalainen, A; Gorza, M; Kremer, LS; et al. Haack, TB; Ignatius, E; Calvo-Garrido, J; Iuso, A; Isohanni, P; Maffezzini, C; Lönnqvist, T; Suomalainen, A; Gorza, M; Kremer, LS; Graf, E; Hartig, M; Berutti, R; Paucar, M; Svenningsson, P; Stranneheim, H; Brandberg, G; Wedell, A; Kurian, MA; Hayflick, SA; Venco, P; Tiranti, V; Strom, TM; Dichgans, M; Horvath, R; Holinski-Feder, E; Freyer, C; Meitinger, T; Prokisch, H; Senderek, J; Wredenberg, A; Carroll, CJ; Klopstock, T (2016) Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy. Am J Hum Genet, 99 (3). pp. 735-743. ISSN 1537-6605 https://doi.org/10.1016/j.ajhg.2016.06.026
SGUL Authors: Carroll, Christopher John

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Abstract

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.

Item Type: Article
Additional Information: © 2016. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
Keywords: Adolescent, Adult, Age of Onset, Ataxia, Autophagosomes, Autophagy, Child, Cognition Disorders, Dysarthria, Dystonia, Female, Fibroblasts, Gait, Humans, Male, Mitochondria, Movement Disorders, Neurodegenerative Diseases, Pedigree, Phenotype, RNA, Messenger, Sequestosome-1 Protein, Supranuclear Palsy, Progressive, Young Adult, Genetics & Heredity, 06 Biological Sciences, 11 Medical And Health Sciences
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Journal or Publication Title: Am J Hum Genet
ISSN: 1537-6605
Language: eng
Dates:
DateEvent
1 September 2016Published
18 August 2016Published Online
27 June 2016Accepted
Publisher License: Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
Projects:
Project IDFunderFunder ID
309548European Research Councilhttp://dx.doi.org/10.13039/501100000781
G1000848Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
109915/Z/15/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
PubMed ID: 27545679
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/109277
Publisher's version: https://doi.org/10.1016/j.ajhg.2016.06.026

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