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

Tobias B. Haack, Erika Ignatius, Javier Calvo-Garrido, Arcangela Iuso, Pirjo Isohanni, Camilla Maffezzini, Tuula Lönnqvist, Anu Suomalainen, Matteo Gorza, Laura S. Kremer, Elisabeth Graf, Monika Hartig, Riccardo Berutti, Martin Paucar, Per Svenningsson, Henrik Stranneheim, Göran Brandberg, Anna Wedell, Manju A. Kurian, Susan A. HayflickPaola Venco, Valeria Tiranti, Tim M. Strom, Martin Dichgans, Rita Horvath, Elke Holinski-Feder, Christoph Freyer, Thomas Meitinger, Holger Prokisch, Jan Senderek, Anna Wredenberg, Christopher J. Carroll, Susan Hayflick

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish (US)
JournalAmerican Journal of Human Genetics
DOIs
StateAccepted/In press - May 17 2016

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Dystonia
Autophagy
Ataxia
Paralysis
Neurodegenerative Diseases
Gait Ataxia
Exome
Osteitis Deformans
Dysarthria
Mitochondria
Proteins
Fibroblasts
Autophagosomes
Cognitive Dysfunction
Frontotemporal Dementia With Motor Neuron Disease

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

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.; Hayflick, Susan.

In: American Journal of Human Genetics, 17.05.2016.

Research output: Contribution to journalArticle

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 & Hayflick, S 2016, 'Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy', American Journal of Human Genetics. https://doi.org/10.1016/j.ajhg.2016.06.026
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. ; Hayflick, Susan. / Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy. In: American Journal of Human Genetics. 2016.
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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.",
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AU - Ignatius, Erika

AU - Calvo-Garrido, Javier

AU - Iuso, Arcangela

AU - Isohanni, Pirjo

AU - Maffezzini, Camilla

AU - Lönnqvist, Tuula

AU - Suomalainen, Anu

AU - Gorza, Matteo

AU - Kremer, Laura S.

AU - Graf, Elisabeth

AU - Hartig, Monika

AU - Berutti, Riccardo

AU - Paucar, Martin

AU - Svenningsson, Per

AU - Stranneheim, Henrik

AU - Brandberg, Göran

AU - Wedell, Anna

AU - Kurian, Manju A.

AU - Hayflick, Susan A.

AU - Venco, Paola

AU - Tiranti, Valeria

AU - Strom, Tim M.

AU - Dichgans, Martin

AU - Horvath, Rita

AU - Holinski-Feder, Elke

AU - Freyer, Christoph

AU - Meitinger, Thomas

AU - Prokisch, Holger

AU - Senderek, Jan

AU - Wredenberg, Anna

AU - Carroll, Christopher J.

AU - Hayflick, Susan

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