Lysosomal storage diseases, including mucopolysaccharidoses, result from genetic defects that impair lysosomal catabolism. Here, we describe two patients from two independent families presenting with progressive psychomotor regression, delayed myelination, brain atrophy, neutropenia, skeletal abnormalities, and mucopolysaccharidosis-like dysmorphic features. Both patients were homozygous for the same intronic variant in VPS16, a gene encoding a subunit of the HOPS and CORVET complexes. The variant impaired normal mRNA splicing and led to an ~85% reduction in VPS16 protein levels in patient-derived fibroblasts. Levels of other HOPS/CORVET subunits, including VPS33A, were similarly reduced, but restored upon re-expression of VPS16. Patient-derived fibroblasts showed defects in the uptake and endosomal trafficking of transferrin as well as accumulation of autophagosomes and lysosomal compartments. Re-expression of VPS16 rescued the cellular phenotypes. Zebrafish with disrupted vps16 expression showed impaired development, reduced myelination, and a similar accumulation of lysosomes and autophagosomes in the brain, particularly in glia cells. This disorder resembles previously reported patients with mutations in VPS33A, thus expanding the family of mucopolysaccharidosis-like diseases that result from mutations in HOPS/CORVET subunits.
|Journal||EMBO Molecular Medicine|
|Publication status||Published - 3 May 2021|
The authors are grateful to the patients and their families. FHS is supported by grants from the Swedish State Support for Clinical Research (ALFGBG‐797811 to FHS), the Swedish Research Council (dnr 2017‐03331) and by the Knut and Alice Wallenberg Foundation via the Wallenberg Centre for Molecular and Translational Medicine at the University of Gothenburg, Sweden. TvH is supported by an Erasmus University Rotterdam fellowship. TSB is supported by the Netherlands Organisation for Scientific Research (ZonMW Veni, grant 91617021), a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation, an Erasmus MC Fellowship 2017, and Erasmus MC Human Disease Model Award 2018. LeS is supported by a LEaDing fellowship from the European Union’s Horizon 2020 research and innovation program, under the Marie Skłodowska‐Curie grant agreement No 707404. KM and JG are supported by grants from the German Research Foundation (Ga354/14‐1).
Publisher Copyright: ©2021 The Authors.