Protein O-mannosyl-transferase TMEM260
dolichyl-phosphate-mannose-protein mannosyltransferase activity
The SHDRA syndrome-associated gene &lt;i&gt;TMEM260&lt;/i&gt; encodes a protein-specific O-mannosyltransferase.
Mutations in the <i>TMEM260</i> gene cause structural heart defects and renal anomalies syndrome, but the function of the encoded protein remains unknown. We previously reported wide occurrence of O-mannose glycans on extracellular immunoglobulin, plexin, transcription factor (IPT) domains found in the hepatocyte growth factor receptor (cMET), macrophage-stimulating protein receptor (RON), and plexin receptors, and further demonstrated that two known protein O-mannosylation systems orchestrated by the POMT1/2 and transmembrane and tetratricopeptide repeat-containing proteins 1-4 gene families were not required for glycosylation of these IPT domains. Here, we report that the <i>TMEM260</i> gene encodes an ER-located protein O-mannosyltransferase that selectively glycosylates IPT domains. We demonstrate that disease-causing <i>TMEM260</i> mutations impair O-mannosylation of IPT domains and that <i>TMEM260</i> knockout in cells results in receptor maturation defects and abnormal growth of 3D cell models. Thus, our study identifies the third protein-specific O-mannosylation pathway in mammals and demonstrates that O-mannosylation of IPT domains serves critical functions during epithelial morphogenesis. Our findings add a new glycosylation pathway and gene to a growing group of congenital disorders of glycosylation.