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.
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.
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.
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.
- early-onset neurodegeneration, ataxia, SQSTM1, autophagy, ubiquitined protein aggregates