Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration

V. Muto, E. Flex, Z. Kupchinsky, G. Primiano, H. Galehdari, M. Dehghani, S. Cecchetti, G. Carpentieri, T. Rizza, N. Mazaheri, A. Sedaghat, M.Y.V. Mehrjardi, A. Traversa, M. Di Nottia, M.M. Kousi, Y. Jamshidi, A. Ciolfi, V. Caputo, R.A. Malamiri, F. PantaleoniS. Martinelli, A.R. Jeffries, J. Zeighami, A. Sherafat, D. Di Giuda, G.R. Shariati, R. Carrozzo, N. Katsanis, R. Maroofian, S. Servidei, M. Tartaglia

Research output: Contribution to journal › Article

Abstract

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.
Original languageEnglish
Pages (from-to)E319-E330
JournalNeurology
Volume91
Issue number4
DOIs
Publication statusPublished - 2018

Fingerprint

Cerebellum
Exome
Autophagy
Zebrafish
Mutation
Phenotype
Cerebellar Diseases
Dystonia
Dyskinesias
Ataxia
Ubiquitin
Heat-Shock Proteins
Natural History
Paralysis
Neurodegenerative Diseases
Atrophy
Exons
Proteins
In Vitro Techniques
Cognitive Dysfunction

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

Cite this

Muto, V., Flex, E., Kupchinsky, Z., Primiano, G., Galehdari, H., Dehghani, M., ... Tartaglia, M. (2018). Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration. Neurology, 91(4), E319-E330. https://doi.org/10.1212/WNL.0000000000005869

Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration. / Muto, V.; Flex, E.; Kupchinsky, Z.; Primiano, G.; Galehdari, H.; Dehghani, M.; Cecchetti, S.; Carpentieri, G.; Rizza, T.; Mazaheri, N.; Sedaghat, A.; Mehrjardi, M.Y.V.; Traversa, A.; Di Nottia, M.; Kousi, M.M.; Jamshidi, Y.; Ciolfi, A.; Caputo, V.; Malamiri, R.A.; Pantaleoni, F.; Martinelli, S.; Jeffries, A.R.; Zeighami, J.; Sherafat, A.; Di Giuda, D.; Shariati, G.R.; Carrozzo, R.; Katsanis, N.; Maroofian, R.; Servidei, S.; Tartaglia, M.

In: Neurology, Vol. 91, No. 4, 2018, p. E319-E330.

Research output: Contribution to journal › Article

Muto, V, Flex, E, Kupchinsky, Z, Primiano, G, Galehdari, H, Dehghani, M, Cecchetti, S, Carpentieri, G, Rizza, T, Mazaheri, N, Sedaghat, A, Mehrjardi, MYV, Traversa, A, Di Nottia, M, Kousi, MM, Jamshidi, Y, Ciolfi, A, Caputo, V, Malamiri, RA, Pantaleoni, F, Martinelli, S, Jeffries, AR, Zeighami, J, Sherafat, A, Di Giuda, D, Shariati, GR, Carrozzo, R, Katsanis, N, Maroofian, R, Servidei, S & Tartaglia, M 2018, 'Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration', Neurology, vol. 91, no. 4, pp. E319-E330. https://doi.org/10.1212/WNL.0000000000005869
Muto V, Flex E, Kupchinsky Z, Primiano G, Galehdari H, Dehghani M et al. Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration. Neurology. 2018;91(4):E319-E330. https://doi.org/10.1212/WNL.0000000000005869
Muto, V. ; Flex, E. ; Kupchinsky, Z. ; Primiano, G. ; Galehdari, H. ; Dehghani, M. ; Cecchetti, S. ; Carpentieri, G. ; Rizza, T. ; Mazaheri, N. ; Sedaghat, A. ; Mehrjardi, M.Y.V. ; Traversa, A. ; Di Nottia, M. ; Kousi, M.M. ; Jamshidi, Y. ; Ciolfi, A. ; Caputo, V. ; Malamiri, R.A. ; Pantaleoni, F. ; Martinelli, S. ; Jeffries, A.R. ; Zeighami, J. ; Sherafat, A. ; Di Giuda, D. ; Shariati, G.R. ; Carrozzo, R. ; Katsanis, N. ; Maroofian, R. ; Servidei, S. ; Tartaglia, M. / Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration. In: Neurology. 2018 ; Vol. 91, No. 4. pp. E319-E330.
@article{88a742c0b8d04fd98b066dcd19aa6f7b,
title = "Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration",
abstract = "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 {\circledC} 2018 American Academy of Neurology.",
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",
author = "V. Muto and E. Flex and Z. Kupchinsky and G. Primiano and H. Galehdari and M. Dehghani and S. Cecchetti and G. Carpentieri and T. Rizza and N. Mazaheri and A. Sedaghat and M.Y.V. Mehrjardi and A. Traversa and {Di Nottia}, M. and M.M. Kousi and Y. Jamshidi and A. Ciolfi and V. Caputo and R.A. Malamiri and F. Pantaleoni and S. Martinelli and A.R. Jeffries and J. Zeighami and A. Sherafat and {Di Giuda}, D. and G.R. Shariati and R. Carrozzo and N. Katsanis and R. Maroofian and S. Servidei and M. Tartaglia",
note = "Cited By :1 Export Date: 11 April 2019 CODEN: NEURA Correspondence Address: Tartaglia, M.; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Ges{\`u}Italy; 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: Universit{\`a} Cattolica del Sacro Cuore Funding details: Kerman University of Medical Sciences Funding details: University of Exeter Funding details: Istituto Superiore di Sanit{\`a} 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 Ges{\`u}; Department of Oncology and Molecular Medicine (E.F., S.M.) and Confocal Microscopy Unit (S.C.), Core Facilities, Istituto Superiore di Sanit{\`a}, 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.), Universit{\`a} 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.), Universit{\`a} “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 Ges{\`u} (Vite Coraggiose) and the Italian Ministry of Health (Ricerca Corrente 2016 and 2017) to M.T. References: Johansen, T., Lamark, T., Selective autophagy mediated by autophagic adapter proteins (2011) Autophagy, 7, pp. 279-296; G{\"o}tzl, J.K., Lang, C.M., Haass, C., Capell, A., Impaired protein degradation in FTLD and related disorders (2016) Ageing Res Rev, 32, pp. 122-139; Frake, R.A., Ricketts, T., Menzies, F.M., Rubinsztein, D.C., Autophagy and neuro-degeneration (2015) J Clin Invest, 125, pp. 65-74; Nixon, R.A., Yang, D.S., Autophagy failure in Alzheimer's disease: Locating the primary defect (2011) Neurobiol Dis, 43, pp. 38-45; Majcher, V., Goode, A., James, V., Layfield, R., Autophagy receptor defects and ALS-FTLD (2015) Mol Cel Neurosci, 66, pp. 43-52; Seibenhener, M.L., Geetha, T., Wooten, M.W., Sequestosome 1/p62: More than just a scaffold (2007) FEBS Lett, 581, pp. 175-179; Katsuragi, Y., Ichimura, Y., Komatsu, M., p62/SQSTM1 functions as a signaling hub and an autophagy adaptor (2015) FEBS J, 282, pp. 4672-4678; Rea, S.L., Majcher, V., Searle, M.S., Layfield, R., SQSTM1 mutations: Bridging paget disease of bone and ALS/FTLD (2014) Exp Cel Res, 325, pp. 27-37; Usategui-Martin, R., Garcia-Aparicio, J., Corral-Gudino, L., Calero-Paniagua, I., Del Pino-Montes, J., Gonz{\'a}lez Sarmiento, R., Polymorphisms in autophagy genes are associated with paget disease of bone (2015) PLoS One, 10; Goode, A., Butler, K., Long, J., Shaw, B., Searle, M.S., Layfield, R., Defective recognition of LC3B by mutant SQSTM1/p62 implicates impairment of autophagy as a pathogenic mechanism in ALS-FTLD (2016) Autophagy, 12, pp. 1094-1104; Haack, T.B., Ignatius, E., Calvo-Garrido, J., Absence of the autophagy adaptor SQSTM1/p62 causes childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy (2016) Am J Hum Genet, 99, pp. 735-743; V{\'a}zquez, C.L., Colombo, M.I., Assays to assess autophagy induction and fusion of autophagic vacuoles with a degradative compartment, using monodansylcadaverine (MDC) and DQ-BSA (2009) Methods Enzymol, 452, pp. 85-95; Carrozzo, R., Torraco, A., Fiermonte, G., Riboflavin responsive mitochondrial myopathy is a new phenotype of dihydrolipoamide dehydrogenase deficiency: The chaperon-like effect of Vitamin B2 (2014) Mitochondrion, 18, pp. 49-57; 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year = "2018",
doi = "10.1212/WNL.0000000000005869",
language = "English",
volume = "91",
pages = "E319--E330",
journal = "Neurology",
issn = "0028-3878",
publisher = "Lippincott Williams and Wilkins",
number = "4",

}

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. References: Johansen, T., Lamark, T., Selective autophagy mediated by autophagic adapter proteins (2011) Autophagy, 7, pp. 279-296; Götzl, J.K., Lang, C.M., Haass, C., Capell, A., Impaired protein degradation in FTLD and related disorders (2016) Ageing Res Rev, 32, pp. 122-139; Frake, R.A., Ricketts, T., Menzies, F.M., Rubinsztein, D.C., Autophagy and neuro-degeneration (2015) J Clin Invest, 125, pp. 65-74; Nixon, R.A., Yang, D.S., Autophagy failure in Alzheimer's disease: Locating the primary defect (2011) Neurobiol Dis, 43, pp. 38-45; Majcher, V., Goode, A., James, V., Layfield, R., Autophagy receptor defects and ALS-FTLD (2015) Mol Cel Neurosci, 66, pp. 43-52; Seibenhener, M.L., Geetha, T., Wooten, M.W., Sequestosome 1/p62: More than just a scaffold (2007) FEBS Lett, 581, pp. 175-179; Katsuragi, Y., Ichimura, Y., Komatsu, M., p62/SQSTM1 functions as a signaling hub and an autophagy adaptor (2015) FEBS J, 282, pp. 4672-4678; Rea, S.L., Majcher, V., Searle, M.S., Layfield, R., SQSTM1 mutations: Bridging paget disease of bone and ALS/FTLD (2014) Exp Cel Res, 325, pp. 27-37; Usategui-Martin, R., Garcia-Aparicio, J., Corral-Gudino, L., Calero-Paniagua, I., Del Pino-Montes, J., González Sarmiento, R., Polymorphisms in autophagy genes are associated with paget disease of bone (2015) PLoS One, 10; Goode, A., Butler, K., Long, J., Shaw, B., Searle, M.S., Layfield, R., Defective recognition of LC3B by mutant SQSTM1/p62 implicates impairment of autophagy as a pathogenic mechanism in ALS-FTLD (2016) Autophagy, 12, pp. 1094-1104; Haack, T.B., Ignatius, E., Calvo-Garrido, J., Absence of the autophagy adaptor SQSTM1/p62 causes childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy (2016) Am J Hum Genet, 99, pp. 735-743; Vázquez, C.L., Colombo, M.I., Assays to assess autophagy induction and fusion of autophagic vacuoles with a degradative compartment, using monodansylcadaverine (MDC) and DQ-BSA (2009) Methods Enzymol, 452, pp. 85-95; Carrozzo, R., Torraco, A., Fiermonte, G., Riboflavin responsive mitochondrial myopathy is a new phenotype of dihydrolipoamide dehydrogenase deficiency: The chaperon-like effect of Vitamin B2 (2014) Mitochondrion, 18, pp. 49-57; Flex, E., Niceta, M., Cecchetti, S., Biallelic mutations in TBCD, encoding the tubulin folding cofactor D, perturb microtubule dynamics and cause early-onset encephalopathy (2016) Am J Hum Genet, 99, pp. 962-973; Davis, E.E., Frangakis, S., Katsanis, N., Interpreting human genetic variation with in vivo zebrafish assays (2014) Biochim Biophys Acta, 1842, pp. 1960-1970; Pankiv, S., Clausen, T.H., Lamark, T., p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy (2007) J Biol Chem, 282, pp. 24131-24145; Bjørkøy, G., Lamark, T., Brech, A., p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on Huntingtin-induced cell death (2005) J Cel Biol, 171, pp. 603-614; Geisler, S., Holmstrom, K.M., Skujat, D., PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1 (2010) Nat Cel Biol, 12, pp. 119-131; Margolin, D.H., Kousi, M., Chan, Y.M., Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination (2013) N Engl J Med, 368, pp. 1992-2003; 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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 -

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Istituto Superiore di Sanita' - Oncologia e medicina molecolare

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