Human ISPD Is a Cytidyltransferase Required for Dystroglycan O-Mannosylation

Moniek Riemersma, D. Sean Froese, Walinka van Tol, Udo F. Engelke, Jolanta Kopec, Monique van Scherpenzeel, Angel Ashikov, Tobias Krojer, Frank von Delft, Marco Tessari, Anna Buczkowska, Ewa Swiezewska, Lucas T. Jae, Thijn R. Brummelkamp, Hiroshi Manya, Tamao Endo, Hans van Bokhoven, Wyatt W. Yue*, Dirk J. Lefeber

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

52 Citations (Web of Science)


A unique, unsolved O-mannosyl glycan on ?-dystroglycan is essential for its interaction with protein?ligands in the extracellular matrix. Defective O-mannosylation leads to a group of muscular dystrophies, called dystroglycanopathies. Mutations in isoprenoid synthase domain containing (ISPD) represent the second most common cause?of these disorders, however, its molecular function remains uncharacterized. The human ISPD (hISPD) crystal structure showed a canonical N-terminal cytidyltransferase domain linked to a C-terminal domain that is absent in cytidyltransferase homologs. Functional studies demonstrated cytosolic localization of hISPD, and cytidyltransferase activity toward pentose phosphates, including ribulose?5-phosphate, ribose 5-phosphate, and ribitol 5-phosphate. Identity of the CDP sugars was confirmed by liquid chromatography quadrupole time-of-flight mass spectrometry and two-dimensional nuclear magnetic resonance spectroscopy. Our combined results indicate that hISPD?is a cytidyltransferase, suggesting the presence of a novel human nucleotide sugar essential for functional ?-dystroglycan O-mannosylation in muscle and brain. Thereby, ISPD deficiency can be added to the growing list of tertiary dystroglycanopathies.
Original languageEnglish
Pages (from-to)1643-1652
JournalChemistry & Biology
Issue number12
Publication statusPublished - 17 Dec 2015

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