title: Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy.
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.
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany. Electronic address: tobias.haack@helmholtz-muenchen.de.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland; Department of Child Neurology, Children's Hospital, University of Helsinki and Helsinki University Hospital, 00029 HUS, Finland.
authors.forename: Erika
authors.initials: E
authors.lastname: Ignatius
authors.affiliation: Department of Molecular Medicine and Surgery, Science for Life Laboratory, Karolinska Institutet, Stockholm 17176, Sweden.
authors.forename: Javier
authors.initials: J
authors.lastname: Calvo-Garrido
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Arcangela
authors.initials: A
authors.lastname: Iuso
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland; Department of Child Neurology, Children's Hospital, University of Helsinki and Helsinki University Hospital, 00029 HUS, Finland.
authors.forename: Pirjo
authors.initials: P
authors.lastname: Isohanni
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 17177, Sweden.
authors.forename: Camilla
authors.initials: C
authors.lastname: Maffezzini
authors.affiliation: Department of Child Neurology, Children's Hospital, University of Helsinki and Helsinki University Hospital, 00029 HUS, Finland.
authors.forename: Tuula
authors.initials: T
authors.lastname: Lönnqvist
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Anu
authors.initials: A
authors.lastname: Suomalainen
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Matteo
authors.initials: M
authors.lastname: Gorza
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Kremer
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Graf
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Hartig
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Berutti
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm 17176, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Paucar
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm 17176, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Svenningsson
authors.affiliation: Department of Molecular Medicine and Surgery, Science for Life Laboratory, Karolinska Institutet, Stockholm 17176, Sweden; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm 17176, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Stranneheim
authors.affiliation: Department of Pediatrics, Falu lasarett, 79182 Falun, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Brandberg
authors.affiliation: Department of Molecular Medicine and Surgery, Science for Life Laboratory, Karolinska Institutet, Stockholm 17176, Sweden; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm 17176, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Wedell
authors.affiliation: Neurosciences Unit, Institute of Child Health, University College London, London WC1N 3BG, UK; Department of Paediatric Neurology, Great Ormond Street Hospital, London WC1N 3BG, UK.
authors.forename: Manju A
authors.initials: MA
authors.lastname: Kurian
authors.affiliation: Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA; Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA; Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Hayflick
authors.affiliation: Unit of Molecular Neurogenetics - Pierfranco and Luisa Mariani Center for the study of Mitochondrial Disorders in Children, IRCCS Foundation Neurological Institute "C. Besta," 20126 Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Venco
authors.affiliation: Unit of Molecular Neurogenetics - Pierfranco and Luisa Mariani Center for the study of Mitochondrial Disorders in Children, IRCCS Foundation Neurological Institute "C. Besta," 20126 Milan, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Tiranti
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Institute for Stroke and Dementia Research, Ludwig-Maximilians-University of Munich, 81377 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany; DZNE - German Center for Neurodegenerative Diseases, 80336 Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Dichgans
authors.affiliation: MGZ - Medical Genetics Center, 80335 Munich, Germany; Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
authors.affiliation: MGZ - Medical Genetics Center, 80335 Munich, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Holinski-Feder
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 17177, Sweden; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm 17176, Sweden.
authors.forename: Christoph
authors.initials: C
authors.lastname: Freyer
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, 80336 Munich, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Senderek
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 17177, Sweden; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm 17176, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Wredenberg
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Carroll
authors.affiliation: Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany; DZNE - German Center for Neurodegenerative Diseases, 80336 Munich, Germany; Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, 80336 Munich, Germany. Electronic address: tklopsto@med.lmu.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001259:Ataxia / Q000150:complications / Q000235:genetics*; D000071182:Autophagosomes / Q000378:metabolism / Q000473:pathology; D001343:Autophagy / Q000235:genetics*; D002648:Child; D003072:Cognition Disorders / Q000235:genetics; D004401:Dysarthria / Q000150:complications / Q000235:genetics; D004421:Dystonia / Q000150:complications / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005684:Gait / Q000235:genetics; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009069:Movement Disorders / Q000150:complications / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000150:complications / Q000235:genetics* / Q000503:physiopathology*; D010375:Pedigree; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D000071456:Sequestosome-1 Protein / Q000172:deficiency* / Q000235:genetics; D013494:Supranuclear Palsy, Progressive / Q000150:complications / Q000235:genetics*; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein