Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration

OBJECTIVE: To characterize clinically and molecularly an early-onset, variablyprogressive neurodegenerative disorder characterized by a cerebellar syndromewith severe ataxia, gaze palsy, dyskinesia, dystonia, and cognitive declineaffecting 11 individuals from 3 consanguineous families.METHODS: We used whole-exome sequencing (WES) (families 1 and 2) and a combinedapproach based on homozygosity mapping and WES (family 3). We performed in vitro studies to explore the effect of the nontruncating SQSTM1 mutation on proteinfunction and the effect of impaired SQSTM1 function on autophagy. We analyzed theconsequences of sqstm1 down-modulation on the structural integrity of thecerebellum in vivo using zebrafish as a model.RESULTS: We identified 3 homozygous inactivating variants, including a splicesite substitution (c.301+2T>A) causing aberrant transcript processing andaccelerated degradation of a resulting protein lacking exon 2, as well as 2truncating changes (c.875_876insT and c.934_936delinsTGA). We show that loss ofSQSTM1 causes impaired production of ubiquitin-positive protein aggregates inresponse to misfolded protein stress and decelerated autophagic flux. Theconsequences of sqstm1 down-modulation on the structural integrity of thecerebellum in zebrafish documented a variable but reproducible phenotypecharacterized by cerebellum anomalies ranging from depletion of axonalconnections to complete atrophy. We provide a detailed clinical characterization of the disorder; the natural history is reported for 2 siblings who have beenfollowed up for >20 years.CONCLUSIONS: This study offers an accurate clinical characterization of thisrecently recognized neurodegenerative disorder caused by biallelic inactivatingmutations in SQSTM1 and links this phenotype to defective selective autophagy.