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 journalArticlepeer-review


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
Issue number4
Publication statusPublished - 2018


  • 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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