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Hum Mol Genet. 2017 Jan 1;26(1):173-183. doi: 10.1093/hmg/ddw377.

Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms.

Author information

Department of Pediatrics, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka, Japan.
Laboratory of Genome Medicine, Clinics of Medical Institute, North East Federal University, Yakutsk, Russia.
Department of Genetics.
Research Center for Autophagy.
Department of Medical Biochemistry.
Department of Cardiology.
Department of Genome Informatics, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka, Japan.
Medical Solutions Division, NEC Corporation, Shiba, Minato-ku, Tokyo, Japan.
Department of Pathology, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka, Japan.
Republican Hospital no. 1, National Medical Center of the Republic of Sakha, Yakutsk, Russia.
Division of Health Science, Child Healthcare and Genetic Science Laboratory, Osaka University Graduate School of Medicine, Yamadaoka, Osaka, Japan.


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.

[Indexed for MEDLINE]

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