The Muscular Dystrophy Gene TMEM5 Encodes a Ribitol ?1,4-Xylosyltransferase Required for the Functional Glycosylation of Dystroglycan.

ABSTRACT: A defect in O-mannosyl glycan is the cause of ?-dystroglycanopathy, a group of congenital muscular dystrophies caused by aberrant ?-dystroglycan (?-DG) glycosylation. Recently, the entire structure of O-mannosyl glycan, [3GlcA?1-3Xyl?1]n-3GlcA?1-4Xyl-Rbo5P-1Rbo5P-3GalNAc?1-3GlcNAc?1-4 (phospho-6)Man?1-, which is required for the binding of ?-DG to extracellular matrix ligands, has been proposed. However, the linkage of the first Xyl residue to ribitol 5-phosphate (Rbo5P) is not clear. TMEM5 is a gene product responsible for ?-dystroglycanopathy and was reported as a potential enzyme involved in this linkage formation, although the experimental evidence is still incomplete. Here, we report that TMEM5 is a xylosyltransferase that forms the Xyl?1-4Rbo5P linkage on O-mannosyl glycan. The anomeric configuration and linkage position of the product (?1,4 linkage) was determined by NMR analysis. The introduction of two missense mutations in TMEM5 found in ?-dystroglycanopathy patients impaired xylosyltransferase activity. Furthermore, the disruption of the TMEM5 gene by CRISPR/Cas9 abrogated the elongation of the (-3GlcA?1-3Xyl?1-) unit on O-mannosyl glycan. Based on these results, we concluded that TMEM5 acts as a UDP-d-xylose:ribitol-5-phosphate ?1,4-xylosyltransferase in the biosynthetic pathway of O-mannosyl glycan.

SUBMITTER: Manya H 

PROVIDER: S-EPMC5114413 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature