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Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy.
Haack, Tobias B; Ignatius, Erika; Calvo-Garrido, Javier; Iuso, Arcangela; Isohanni, Pirjo; Maffezzini, Camilla; Lönnqvist, Tuula; Suomalainen, Anu; Gorza, Matteo; Kremer, Laura S; Graf, Elisabeth; Hartig, Monika; Berutti, Riccardo; Paucar, Martin; Svenningsson, Per; Stranneheim, Henrik; Brandberg, Göran; Wedell, Anna; Kurian, Manju A; Hayflick, Susan A; Venco, Paola; Tiranti, Valeria; Strom, Tim M; Dichgans, Martin; Horvath, Rita; Holinski-Feder, Elke; Freyer, Christoph; Meitinger, Thomas; Prokisch, Holger; Senderek, Jan; Wredenberg, Anna; Carroll, Christopher J; Klopstock, Thomas.
Afiliación
  • Haack TB; 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.
  • Ignatius E; 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.
  • Calvo-Garrido J; Department of Molecular Medicine and Surgery, Science for Life Laboratory, Karolinska Institutet, Stockholm 17176, Sweden.
  • Iuso A; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • Isohanni P; 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.
  • Maffezzini C; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 17177, Sweden.
  • Lönnqvist T; Department of Child Neurology, Children's Hospital, University of Helsinki and Helsinki University Hospital, 00029 HUS, Finland.
  • Suomalainen A; Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland.
  • Gorza M; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • Kremer LS; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • Graf E; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • Hartig M; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
  • Berutti R; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • Paucar M; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm 17176, Sweden.
  • Svenningsson P; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm 17176, Sweden.
  • Stranneheim H; 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.
  • Brandberg G; Department of Pediatrics, Falu lasarett, 79182 Falun, Sweden.
  • Wedell A; 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.
  • Kurian MA; 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.
  • Hayflick SA; 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.
  • Venco P; 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.
  • Tiranti V; 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.
  • Strom TM; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • Dichgans M; 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.
  • Horvath R; MGZ - Medical Genetics Center, 80335 Munich, Germany; Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
  • Holinski-Feder E; MGZ - Medical Genetics Center, 80335 Munich, Germany.
  • Freyer C; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 17177, Sweden; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm 17176, Sweden.
  • Meitinger T; 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.
  • Prokisch H; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • Senderek J; Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, 80336 Munich, Germany.
  • Wredenberg A; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 17177, Sweden; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm 17176, Sweden.
  • Carroll CJ; Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland.
  • Klopstock T; 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.
Am J Hum Genet ; 99(3): 735-743, 2016 09 01.
Article en En | MEDLINE | ID: mdl-27545679
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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ataxia / Autofagia / Parálisis Supranuclear Progresiva / Enfermedades Neurodegenerativas / Distonía / Proteína Sequestosoma-1 Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Adolescent / Adult / Child / Female / Humans / Male Idioma: En Revista: Am J Hum Genet Año: 2016 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ataxia / Autofagia / Parálisis Supranuclear Progresiva / Enfermedades Neurodegenerativas / Distonía / Proteína Sequestosoma-1 Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Adolescent / Adult / Child / Female / Humans / Male Idioma: En Revista: Am J Hum Genet Año: 2016 Tipo del documento: Article