A de novo VPS16 missense variant blocks autophagic flux and extends DYT-VPS16 into infancy

Autophagy terminates in the degradation of cargo delivered by fusion of the autophagosome with the lysosome, a step tethered by the homotypic fusion and vacuole protein sorting (HOPS) complex. Heterozygous loss-of-function variants in VPS16, which encodes a core HOPS subunit, cause autosomal dominant DYT-VPS16 dystonia. The pathogenicity of missense alleles has remained uncertain due to a lack of mechanistic data from patient-derived cells. We summarize our recent report of the youngest individual with DYT-VPS16 described to date. This child presented with infantile-onset generalized dystonia caused by a de novo VPS16 missense variant, p. Ala466Thr. Patient-derived fibroblasts accumulate enlarged, stalled autolysosomes and show concurrent elevation of SQSTM1/p62 and the MAP1LC3B/LC3B-II:LC3B-I ratio, consistent with a block in autophagic flux. We discuss the consequences for variant interpretation, describe a previously unrecognized caudate-predominant neuroimaging correlate, and speculate on why striatal neurons are selectively vulnerable to HOPS dysfunction. Abbreviations: HOPS: homotypic fusion and vacuole protein sorting; LOF: loss-of-function; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; SQSTM1: sequestosome 1.