| RRC ID |
47720
|
| 著者 |
Kondo H, Maksimova N, Otomo T, Kato H, Imai A, Asano Y, Kobayashi K, Nojima S, Nakaya A, Hamada Y, Irahara K, Gurinova E, Sukhomyasova A, Nogovicina A, Savvina M, Yoshimori T, Ozono K, Sakai N.
|
| タイトル |
Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms.
|
| ジャーナル |
Hum Mol Genet
|
| 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.
|
| 巻・号 |
26(1)
|
| ページ |
173-183
|
| 公開日 |
2017-1-1
|
| DOI |
10.1093/hmg/ddw377
|
| PII |
ddw377
|
| PMID |
28013294
|
| MeSH |
Adolescent
Adult
Case-Control Studies
Cells, Cultured
Child
Female
Fibroblasts / metabolism
Fibroblasts / pathology
Glycosaminoglycans / metabolism*
Humans
Male
Mucopolysaccharidoses / genetics*
Mucopolysaccharidoses / metabolism*
Mutation / genetics*
Pedigree
Severity of Illness Index
Vesicular Transport Proteins / genetics*
Young Adult
|
| IF |
5.101
|
| 引用数 |
19
|
|
WOS 分野
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
GENETICS & HEREDITY
|
| リソース情報 |
| 遺伝子材料 |
Genome Network Project Human cDNA IRAK013C20 (HGX005268) |
