Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration
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.