Mutation inVPS33Aaffects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms

Abstract

Mucopolysaccharidoses (MPS) are a group of genetic deficiencies of lysosomal enzymes that catabolize glycosaminoglycans (GAG). Here we describe a novel MPS-like disease caused by a specific mutation in the VPS33A gene. We identified several Yakut patients showing typical manifestations of MPS: coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, mental retardation, and excess secretion of urinary GAG. However, these patients could not be diagnosed enzymatically as MPS. They showed extremely high levels of plasma heparan sulphate (HS, one of GAG); 60 times the normal reference range and 6 times that of MPS patients. Additionally, most patients developed heart, kidney, and hematopoietic disorders, which are not typical symptoms for conventional MPS, leading to a fatal outcome between 1 and 2-years old. Using whole exome and Sanger sequencing, we identified homozygous c.1492C > T (p.Arg498Trp) mutations in the VPS33A gene of 13 patients. VPS33A is involved in endocytic and autophagic pathways, but the identified mutation did not affect either of these pathways. Lysosomal over-acidification and HS accumulation were detected in patient-derived and VPS33A-depleted cells, suggesting a novel role of this gene in lysosomal functions. We hence propose a new type of MPS that is not caused by an enzymatic deficiency.

VPS41recessive mutation causes ataxia and dystonia with retinal dystrophy and mental retardation by inhibiting HOPS function and mTORC1 signaling

“…Currently, patients with mutations in HOPS core components VPS11, VPS16 and VPS33A have been reported in literature, which all show a neurodegenerative phenotype (11,(67)(68)(69)(70)(71)(72)(73)(74). Moreover, during our studies, a third patient with compound heterozygote mutations in VPS41 was identified (Personal communication by I. Stolte-Dijkstra, University Medical Center Groningen), bearing the VPS41 R662* mutation as well as a missense mutation (VPS41 H466R ), and displaying a similar neurological phenotype.…”

CORVET, CHEVI and HOPS – multisubunit tethers of the endo-lysosomal system in health and disease

“…Mutations in CHEVI or HOPS components commonly cause neurological defects in the C. elegans, D. melanogaster, zebrafish and mice animal models (Fernandes et al, 2014;Harrington et al, 2012;Kim et al, 2004;Peng et al, 2012b;Suzuki et al, 2003;Zhang et al, 2016). Patients carrying mutations in the core components Vps11, Vps16 or Vps33A (Cai et al, 2016;Edvardson et al, 2015;Hörtnagel et al, 2016;Kondo et al, 2017;Zhang et al, 2016) or ARC-causing mutations in the CHEVI subunits also show neurological symptoms (Eastham et al, 2001). Intriguingly, mutations in Vps3 or Vps8 seemingly do not impact neuronal function (Lorincz et al, 2016).…”

VPS18 recruits VPS41 to the human HOPS complex via a RING-RING interaction

“…However, there is evidence of evolutionary divergence within the membrane trafficking system. Metazoan VPS33A and VPS33B are both homologs of the yeast HOPS subunit Vps33 (17), but only VPS33A is found in human HOPS (6,11,18) and mutations in these two homologs generate significantly different phenotypes (19)(20)(21)(22)(23). Also, Vps41 in yeast has been shown to bind directly to Ypt7 (24), but in humans it appears that the analogous interaction (with Rab7) is mediated by an additional protein, RILP (14).…”