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The VPS33A gene encodes a Sec1/Munc18 family member integral to both the CORVET and HOPS membrane-tethering complexes required for endolysosomal and autophagosome-lysosome fusion. Biallelic pathogenic missense variants in VPS33A cause mucopolysaccharidosis-plus syndrome (MPS-PS), an autosomal recessive lysosomal storage disorder characterized by conventional mucopolysaccharidosis features plus congenital heart defects, renal tubular dysfunction and hematopoietic involvement ([PMID:31936524]).
Genetic evidence includes the recurrent Yakut founder variant c.1492C>T (p.Arg498Trp) and a novel Polish homozygous c.599G>C (p.Arg200Pro), with over 63 probands described to date across Yakut, Turkish and non-consanguineous populations ([PMID:36232726], [PMID:35327996]). Inheritance is autosomal recessive, with homozygous or compound heterozygous missense changes disrupting VPS33A function.
Segregation analyses confirm co-segregation of these variants with disease in multiple families, and the p.Arg498Trp allele demonstrates a clear founder effect in Yakutia. No healthy homozygotes have been reported, supporting pathogenicity of these variants.
Clinically, MPS-PS presents in infancy with coarse facies, dysostosis multiplex, abnormal heart morphology (HP:0001627), fetal ascites (HP:0001791), hepatosplenomegaly, recurrent joint effusions and peripheral edemas; most patients die within the first two years of life ([PMID:35327996]). A longer-surviving juvenile form with attenuated severity has been reported in a patient with p.Arg200Pro, who exhibited residual endolysosomal trafficking and milder clinical course ([PMID:36153662]).
Functional studies of patient fibroblasts reveal normal lysosomal hydrolase activities but pronounced vacuolation, excess urinary dermatan and heparan sulphate, impaired glycosphingolipid trafficking, and markedly reduced VPS33A protein due to proteasomal degradation. Treatment with the proteasome inhibitor bortezomib or glucosylceramide synthesis inhibitor eliglustat partially rescues trafficking defects, confirming a loss-of-function mechanism ([PMID:31070736], [PMID:36153662]).
Together, these data meet criteria for a definitive gene–disease association: autosomal recessive inheritance, >60 well-phenotyped probands, recurrent and novel missense variants, segregation in multiple families, and concordant experimental evidence. Diagnostic confirmation relies on molecular testing for VPS33A variants, and emerging functional rescue strategies offer promising therapeutic avenues. Key Take-home: Biallelic VPS33A variants definitively cause MPS-PS, enabling accurate diagnosis and informing future therapy development.
Gene–Disease AssociationDefinitiveOver 63 probands across Yakut, Turkish and non-consanguineous populations with detailed phenotyping and functional concordance Genetic EvidenceStrongAutosomal recessive inheritance with >63 unrelated probands, recurrent founder and novel missense variants, confirmed co-segregation Functional EvidenceModeratePatient fibroblast assays show impaired endolysosomal trafficking, vacuolation, reduced VPS33A abundance and rescue by proteasome and glucosylceramide synthesis inhibitors |