Abstract
Original language | English |
---|---|
Pages (from-to) | E319-E330 |
Journal | Neurology |
Volume | 91 |
Issue number | 4 |
DOIs | |
Publication status | Published - 2018 |
Keywords
- sequestosome 1
- adolescent
- adult
- alternative RNA splicing
- animal experiment
- Article
- ataxia
- autophagy
- cerebellum disease
- clinical article
- clinical feature
- cognitive defect
- cohort analysis
- controlled study
- disease exacerbation
- disease severity
- down regulation
- dyskinesia
- dystonia
- exon
- female
- follow up
- gaze paralysis
- gene mapping
- gene mutation
- homozygosity
- human
- in vitro study
- in vivo study
- male
- molecular pathology
- nerve degeneration
- nonhuman
- phenotype
- priority journal
- protein degradation
- protein depletion
- protein function
- SQSTM1 gene
- ubiquitination
- whole exome sequencing
- zebra fish
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Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration. / Muto, V.; Flex, E.; Kupchinsky, Z. et al.
In: Neurology, Vol. 91, No. 4, 2018, p. E319-E330.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration
AU - Muto, V.
AU - Flex, E.
AU - Kupchinsky, Z.
AU - Primiano, G.
AU - Galehdari, H.
AU - Dehghani, M.
AU - Cecchetti, S.
AU - Carpentieri, G.
AU - Rizza, T.
AU - Mazaheri, N.
AU - Sedaghat, A.
AU - Mehrjardi, M.Y.V.
AU - Traversa, A.
AU - Di Nottia, M.
AU - Kousi, M.M.
AU - Jamshidi, Y.
AU - Ciolfi, A.
AU - Caputo, V.
AU - Malamiri, R.A.
AU - Pantaleoni, F.
AU - Martinelli, S.
AU - Jeffries, A.R.
AU - Zeighami, J.
AU - Sherafat, A.
AU - Di Giuda, D.
AU - Shariati, G.R.
AU - Carrozzo, R.
AU - Katsanis, N.
AU - Maroofian, R.
AU - Servidei, S.
AU - Tartaglia, M.
N1 - Cited By :1 Export Date: 11 April 2019 CODEN: NEURA Correspondence Address: Tartaglia, M.; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino GesùItaly; email: marco.tartaglia@opbg.net Funding details: School of Medicine, Duke University Funding details: Shahid Chamran University of Ahvaz Funding details: Center for Outcomes Research and Evaluation, Yale School of Medicine Funding details: Shahid Beheshti University of Medical Sciences Funding details: Center for Clinical and Translational Research Funding details: St. George's, University of London Funding details: Faculty of Arts and Sciences Funding details: Ahvaz Jundishapur University of Medical Sciences Funding details: Università Cattolica del Sacro Cuore Funding details: Kerman University of Medical Sciences Funding details: University of Exeter Funding details: Istituto Superiore di Sanità Funding details: Department of Neurology, University of Pittsburgh Funding text 1: From the Genetics and Rare Diseases Research Division (V.M., G.C., T.R., M.D.N., A.C., F.P., R.C., M.T.), Ospedale Pediatrico Bambino Gesù; Department of Oncology and Molecular Medicine (E.F., S.M.) and Confocal Microscopy Unit (S.C.), Core Facilities, Istituto Superiore di Sanità, Rome, Italy; Center for Human Disease Modeling (Z.K., M.M.K., N.K.), Duke University School of Medicine, Durham, NC; Institutes of Neurology (G.P., S.S.) and Nuclear Medicine (D.D.G.), Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy; Department of Genetics (H.G., N.M.), Faculty of Science, Shahid Chamran University of Ahvaz; Narges Medical Genetics and Prenatal Diagnosis Laboratory (H.G., N.M., A. Sedaghat, J.Z., G.R.S.), Kianpars, Ahvaz; Research and Clinical Center for Infertility (M.D.), Yazd Reproductive Sciences Institute, Medical Genetics Research Centre (M.D., M.Y.V.M.), and Department of Medical Genetics (M.Y.V.M.), Shahid Sadoughi University of Medical Sciences, Yazd, Iran; Department of Experimental Medicine (A.T., V.C.), Università “Sapienza,” Rome, Italy; Genetics and Molecular Cell Sciences Research Centre (Y.J., R.M.), St. George’s University of London, UK; Department of Paediatric Neurology (R.A.M.), Golestan Medical, Educational, and Research Center, and Department of Medical Genetics (G.R.S.), Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Iran; University of Exeter Medical School (A.R.J.), RILD, Royal Devon & Exeter Hospital, UK; and Department of Neurology (A. Sherafat), Kerman University of Medical Sciences, Iran. Funding text 2: This work was supported in part by Fondazione Bambino Gesù (Vite Coraggiose) and the Italian Ministry of Health (Ricerca Corrente 2016 and 2017) to M.T. 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PY - 2018
Y1 - 2018
N2 - Objective: To characterize clinically and molecularly an early-onset, variably progressive neurodegenerative disorder characterized by a cerebellar syndrome with severe ataxia, gaze palsy, dyskinesia, dystonia, and cognitive decline affecting 11 individuals from 3 consanguineous families. Methods: We used whole-exome sequencing (WES) (families 1 and 2) and a combined approach based on homozygosity mapping and WES (family 3). We performed in vitro studies to explore the effect of the nontruncating SQSTM1 mutation on protein function and the effect of impaired SQSTM1 function on autophagy. We analyzed the consequences of sqstm1 down-modulation on the structural integrity of the cerebellum in vivo using zebrafish as a model. Results: We identified 3 homozygous inactivating variants, including a splice site substitution (c.301+2T>A) causing aberrant transcript processing and accelerated degradation of a resulting protein lacking exon 2, as well as 2 truncating changes (c.875-876insT and c.934-936delin-sTGA). We show that loss of SQSTM1 causes impaired production of ubiquitin-positive protein aggregates in response to misfolded protein stress and decelerated autophagic flux. The consequences of sqstm1 down-modulation on the structural integrity of the cerebellum in zebrafish documented a variable but reproducible phenotype characterized by cerebellum anomalies ranging from depletion of axonal connections to complete atrophy. We provide a detailed clinical characterization of the disorder; the natural history is reported for 2 siblings who have been followed up for >20 years. Conclusions: This study offers an accurate clinical characterization of this recently recognized neurode-generative disorder caused by biallelic inactivating mutations in SQSTM1 and links this phenotype to defective selective autophagy. Copyright © 2018 American Academy of Neurology.
AB - Objective: To characterize clinically and molecularly an early-onset, variably progressive neurodegenerative disorder characterized by a cerebellar syndrome with severe ataxia, gaze palsy, dyskinesia, dystonia, and cognitive decline affecting 11 individuals from 3 consanguineous families. Methods: We used whole-exome sequencing (WES) (families 1 and 2) and a combined approach based on homozygosity mapping and WES (family 3). We performed in vitro studies to explore the effect of the nontruncating SQSTM1 mutation on protein function and the effect of impaired SQSTM1 function on autophagy. We analyzed the consequences of sqstm1 down-modulation on the structural integrity of the cerebellum in vivo using zebrafish as a model. Results: We identified 3 homozygous inactivating variants, including a splice site substitution (c.301+2T>A) causing aberrant transcript processing and accelerated degradation of a resulting protein lacking exon 2, as well as 2 truncating changes (c.875-876insT and c.934-936delin-sTGA). We show that loss of SQSTM1 causes impaired production of ubiquitin-positive protein aggregates in response to misfolded protein stress and decelerated autophagic flux. The consequences of sqstm1 down-modulation on the structural integrity of the cerebellum in zebrafish documented a variable but reproducible phenotype characterized by cerebellum anomalies ranging from depletion of axonal connections to complete atrophy. We provide a detailed clinical characterization of the disorder; the natural history is reported for 2 siblings who have been followed up for >20 years. Conclusions: This study offers an accurate clinical characterization of this recently recognized neurode-generative disorder caused by biallelic inactivating mutations in SQSTM1 and links this phenotype to defective selective autophagy. Copyright © 2018 American Academy of Neurology.
KW - sequestosome 1
KW - adolescent
KW - adult
KW - alternative RNA splicing
KW - animal experiment
KW - Article
KW - ataxia
KW - autophagy
KW - cerebellum disease
KW - clinical article
KW - clinical feature
KW - cognitive defect
KW - cohort analysis
KW - controlled study
KW - disease exacerbation
KW - disease severity
KW - down regulation
KW - dyskinesia
KW - dystonia
KW - exon
KW - female
KW - follow up
KW - gaze paralysis
KW - gene mapping
KW - gene mutation
KW - homozygosity
KW - human
KW - in vitro study
KW - in vivo study
KW - male
KW - molecular pathology
KW - nerve degeneration
KW - nonhuman
KW - phenotype
KW - priority journal
KW - protein degradation
KW - protein depletion
KW - protein function
KW - SQSTM1 gene
KW - ubiquitination
KW - whole exome sequencing
KW - zebra fish
U2 - 10.1212/WNL.0000000000005869
DO - 10.1212/WNL.0000000000005869
M3 - Article
VL - 91
SP - E319-E330
JO - Neurology
JF - Neurology
SN - 0028-3878
IS - 4
ER -