The lysosomal disease caused by mutant VPS33A ...

• Main Authors: Pavlova, Elena, Shatunov, Aleksey, Wartosch, Lena, Moskvina, Alena, Nikolaeva, Lena, Bright, Nicholas, Tylee, Karen, Church, Heather, Ballabio, Andrea, Luzio, J Paul, Cox, Timothy
• Format: Article in Journal/Newspaper
• Language: English
• Published: Oxford University Press 2019
• Subjects: Antigens, CD; Bortezomib; Carbohydrate Metabolism, Inborn Errors; Cells, Cultured; Endocytosis; Female; Fibroblasts; HeLa Cells; Humans; Infant; Lactosylceramides; Lysosomes; Male; Mucopolysaccharidoses; Mutation, Missense; Phenotype; Proteasome Inhibitors; Protein Conformation; Pyrrolidines; Siberia; Vesicular Transport Proteins; Exome Sequencing; Yakuts
• Online Access: https://dx.doi.org/10.17863/cam.38567; https://www.repository.cam.ac.uk/handle/1810/291395

A rare lysosomal disease resembling a mucopolysaccharidosis with unusual systemic features, including renal disease and platelet dysfunction, caused by the defect in a conserved region of the VPS33A gene on human chromosome 12q24.31, occurs in Yakuts – a nomadic Turkic ethnic group of Southern Siberia. VPS33A is a core component of the class C core vacuole/endosome tethering (CORVET) and the homotypic fusion and protein sorting (HOPS) complexes, which have essential functions in the endocytic pathway. Here we show that cultured fibroblasts from patients with this disorder have morphological changes: vacuolation with disordered endosomal/lysosomal compartments and - common to sphingolipid diseases - abnormal endocytic trafficking of lactosylceramide. Urine glycosaminoglycan studies revealed a pathological excess of sialylated conjugates as well as dermatan- and heparan sulphate. Lipidomic screening showed elevated β-D-galactosylsphingosine with unimpaired activity of cognate lysosomal hydrolases. The 3D ...