Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration

Valentina Muto, Elisabetta Flex, Zachary Kupchinsky, Guido Primiano, Hamid Galehdari, Mohammadreza Dehghani, Serena Cecchetti, Giovanna Carpentieri, Teresa Rizza, Neda Mazaheri, Alireza Sedaghat, Mohammad Yahya Vahidi Mehrjardi, Alice Traversa, Michela Di Nottia, Maria M Kousi, Yalda Jamshidi, Andrea Ciolfi, Viviana Caputo, Reza Azizi Malamiri, Francesca Pantaleoni & 11 others Simone Martinelli, Aaron R Jeffries, Jawaher Zeighami, Amir Sherafat, Daniela Di Giuda, Gholam Reza Shariati, Rosalba Carrozzo, Nicholas Katsanis, Reza Maroofian, Serenella Servidei, Marco Tartaglia

Research output: Contribution to journalArticle

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_936delinsTGA). 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 neurodegenerative disorder caused by biallelic inactivating mutations in SQSTM1 and links this phenotype to defective selective autophagy.

Original languageEnglish
Pages (from-to)e319-e330
JournalNeurology
Volume91
Issue number4
DOIs
Publication statusPublished - Jul 24 2018

Fingerprint

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

Cite this

Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration. / Muto, Valentina; Flex, Elisabetta; Kupchinsky, Zachary; Primiano, Guido; Galehdari, Hamid; Dehghani, Mohammadreza; Cecchetti, Serena; Carpentieri, Giovanna; Rizza, Teresa; Mazaheri, Neda; Sedaghat, Alireza; Vahidi Mehrjardi, Mohammad Yahya; Traversa, Alice; Di Nottia, Michela; Kousi, Maria M; Jamshidi, Yalda; Ciolfi, Andrea; Caputo, Viviana; Malamiri, Reza Azizi; Pantaleoni, Francesca; Martinelli, Simone; Jeffries, Aaron R; Zeighami, Jawaher; Sherafat, Amir; Di Giuda, Daniela; Shariati, Gholam Reza; Carrozzo, Rosalba; Katsanis, Nicholas; Maroofian, Reza; Servidei, Serenella; Tartaglia, Marco.

In: Neurology, Vol. 91, No. 4, 24.07.2018, p. e319-e330.

Research output: Contribution to journalArticle

Muto, V, Flex, E, Kupchinsky, Z, Primiano, G, Galehdari, H, Dehghani, M, Cecchetti, S, Carpentieri, G, Rizza, T, Mazaheri, N, Sedaghat, A, Vahidi Mehrjardi, MY, 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, Valentina ; Flex, Elisabetta ; Kupchinsky, Zachary ; Primiano, Guido ; Galehdari, Hamid ; Dehghani, Mohammadreza ; Cecchetti, Serena ; Carpentieri, Giovanna ; Rizza, Teresa ; Mazaheri, Neda ; Sedaghat, Alireza ; Vahidi Mehrjardi, Mohammad Yahya ; Traversa, Alice ; Di Nottia, Michela ; Kousi, Maria M ; Jamshidi, Yalda ; Ciolfi, Andrea ; Caputo, Viviana ; Malamiri, Reza Azizi ; Pantaleoni, Francesca ; Martinelli, Simone ; Jeffries, Aaron R ; Zeighami, Jawaher ; Sherafat, Amir ; Di Giuda, Daniela ; Shariati, Gholam Reza ; Carrozzo, Rosalba ; Katsanis, Nicholas ; Maroofian, Reza ; Servidei, Serenella ; Tartaglia, Marco. / Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration. In: Neurology. 2018 ; Vol. 91, No. 4. pp. e319-e330.
@article{0fe2555f5afd44e9b23aa75f74cb71d8,
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_936delinsTGA). 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 neurodegenerative disorder caused by biallelic inactivating mutations in SQSTM1 and links this phenotype to defective selective autophagy.",
author = "Valentina Muto and Elisabetta Flex and Zachary Kupchinsky and Guido Primiano and Hamid Galehdari and Mohammadreza Dehghani and Serena Cecchetti and Giovanna Carpentieri and Teresa Rizza and Neda Mazaheri and Alireza Sedaghat and {Vahidi Mehrjardi}, {Mohammad Yahya} and Alice Traversa and {Di Nottia}, Michela and Kousi, {Maria M} and Yalda Jamshidi and Andrea Ciolfi and Viviana Caputo and Malamiri, {Reza Azizi} and Francesca Pantaleoni and Simone Martinelli and Jeffries, {Aaron R} and Jawaher Zeighami and Amir Sherafat and {Di Giuda}, Daniela and Shariati, {Gholam Reza} and Rosalba Carrozzo and Nicholas Katsanis and Reza Maroofian and Serenella Servidei and Marco Tartaglia",
note = "{\circledC} 2018 American Academy of Neurology.",
year = "2018",
month = "7",
day = "24",
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, Valentina

AU - Flex, Elisabetta

AU - Kupchinsky, Zachary

AU - Primiano, Guido

AU - Galehdari, Hamid

AU - Dehghani, Mohammadreza

AU - Cecchetti, Serena

AU - Carpentieri, Giovanna

AU - Rizza, Teresa

AU - Mazaheri, Neda

AU - Sedaghat, Alireza

AU - Vahidi Mehrjardi, Mohammad Yahya

AU - Traversa, Alice

AU - Di Nottia, Michela

AU - Kousi, Maria M

AU - Jamshidi, Yalda

AU - Ciolfi, Andrea

AU - Caputo, Viviana

AU - Malamiri, Reza Azizi

AU - Pantaleoni, Francesca

AU - Martinelli, Simone

AU - Jeffries, Aaron R

AU - Zeighami, Jawaher

AU - Sherafat, Amir

AU - Di Giuda, Daniela

AU - Shariati, Gholam Reza

AU - Carrozzo, Rosalba

AU - Katsanis, Nicholas

AU - Maroofian, Reza

AU - Servidei, Serenella

AU - Tartaglia, Marco

N1 - © 2018 American Academy of Neurology.

PY - 2018/7/24

Y1 - 2018/7/24

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_936delinsTGA). 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 neurodegenerative disorder caused by biallelic inactivating mutations in SQSTM1 and links this phenotype to defective selective autophagy.

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_936delinsTGA). 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 neurodegenerative disorder caused by biallelic inactivating mutations in SQSTM1 and links this phenotype to defective selective autophagy.

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 -