학술논문
The SHDRA syndrome-associated gene TMEM260 encodes a protein-specific O-mannosyltransferase.
Document Type
Article
Author
Larsen, Ida Signe Bohse; Povolo, Lorenzo; Luping Zhou; Weihua Tian; Mygind, Kasper Johansen; Hintze, John; Chen Jiang; Hartill, Verity; Prescott, Katrina; Johnson, Colin A.; Mullegama, Sureni V.; McConkie-Rosell, Allyn; McDonald, Marie; Hansen, Lars; Vakhrushev, Sergey Y.; Schjoldager, Katrine T.; Clausen, Henrik; Worzfeld, Thomas; Joshi, Hiren J.; Halim, Adnan
Source
Subject
*MET receptor
*CELL receptors
*PROTEIN receptors
*GENE families
*TRANSCRIPTION factors
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Language
ISSN
0027-8424
Abstract
Mutations in the TMEM260 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 TMEM260 gene encodes an ER-located protein O-mannosyltransferase that selectively glycosylates IPT domains. We demonstrate that disease-causing TMEM260 mutations impair O-mannosylation of IPT domains and that TMEM260 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. [ABSTRACT FROM AUTHOR]