TY - JOUR
T1 - Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy
AU - Haack, Tobias B B.
AU - Iuso, Arcangela
AU - Kremer, Laura S S.
AU - Hartig, Monika
AU - Strom, Tim M M.
AU - Meitinger, Thomas
AU - Prokisch, Holger
AU - Gorza, Matteo
AU - Graf, Elisabeth
AU - Berutti, Riccardo
AU - Ignatius, Erika
AU - Isohanni, Pirjo
AU - Suomalainen, Anu
AU - Carroll, Christopher J J.
AU - Lönnqvist, Tuula
AU - Calvo-Garrido, Javier
AU - Stranneheim, Henrik
AU - Wedell, Anna
AU - Maffezzini, Camilla
AU - Freyer, Christoph
AU - Wredenberg, Anna
AU - Paucar, Martin
AU - Svenningsson, Per
AU - Brandberg, Göran
AU - Kurian, Manju A A.
AU - Hayflick, Susan A A.
AU - Hayflick, Susan A A.
AU - Venco, Paola
AU - Tiranti, Valeria
AU - Dichgans, Martin
AU - Klopstock, Thomas
AU - Horvath, Rita
AU - Holinski-Feder, Elke
AU - Senderek, Jan
N1 - Publisher Copyright:
© 2016 American Society of Human Genetics
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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.
AB - 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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U2 - 10.1016/j.ajhg.2016.06.026
DO - 10.1016/j.ajhg.2016.06.026
M3 - Article
C2 - 27545679
AN - SCOPUS:84996806746
SN - 0002-9297
VL - 99
SP - 735
EP - 743
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 3
ER -