title: Mutation in VPS33A affects 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.
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka, Japan.
authors.forename: Hidehito
authors.initials: H
authors.lastname: Kondo
authors.affiliation: Laboratory of Genome Medicine, Clinics of Medical Institute, North East Federal University, Yakutsk, Russia.
authors.forename: Nadezda
authors.initials: N
authors.lastname: Maksimova
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka, Japan.|Department of Genetics.|Research Center for Autophagy.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Otomo
authors.affiliation: Department of Medical Biochemistry.
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Kato
authors.affiliation: Department of Cardiology.|Department of Genome Informatics, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Imai
authors.affiliation: Department of Cardiology.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Asano
authors.affiliation: Department of Genome Informatics, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka, Japan.|Medical Solutions Division, NEC Corporation, Shiba, Minato-ku, Tokyo, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Pathology, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nojima
authors.affiliation: Department of Genome Informatics, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Nakaya
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Hamada
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Irahara
authors.affiliation: Republican Hospital no. 1, National Medical Center of the Republic of Sakha, Yakutsk, Russia.
authors.forename: Elizaveta
authors.initials: E
authors.lastname: Gurinova
authors.affiliation: Laboratory of Genome Medicine, Clinics of Medical Institute, North East Federal University, Yakutsk, Russia.|Republican Hospital no. 1, National Medical Center of the Republic of Sakha, Yakutsk, Russia.
authors.forename: Aitalina
authors.initials: A
authors.lastname: Sukhomyasova
authors.affiliation: Republican Hospital no. 1, National Medical Center of the Republic of Sakha, Yakutsk, Russia.
authors.forename: Anna
authors.initials: A
authors.lastname: Nogovicina
authors.affiliation: Laboratory of Genome Medicine, Clinics of Medical Institute, North East Federal University, Yakutsk, Russia.
authors.forename: Mira
authors.initials: M
authors.lastname: Savvina
authors.affiliation: Department of Genetics.|Research Center for Autophagy.
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Yoshimori
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ozono
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka, Japan.|Division of Health Science, Child Healthcare and Genetic Science Laboratory, Osaka University Graduate School of Medicine, Yamadaoka, Osaka, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Sakai
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006025:Glycosaminoglycans / Q000378:metabolism*; D006801:Humans; D008297:Male; D009083:Mucopolysaccharidoses / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D012720:Severity of Illness Index; D033921:Vesicular Transport Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D006025:Glycosaminoglycans; C424440:VPS33A protein, human; D033921:Vesicular Transport Proteins