The SHDRA syndrome-associated gene TMEM260 encodes a protein-specific O-mannosyltransferase

Author:

Larsen Ida Signe Bohse1,Povolo Lorenzo1ORCID,Zhou Luping2,Tian Weihua1,Mygind Kasper Johansen1ORCID,Hintze John1,Jiang Chen2,Hartill Verity34,Prescott Katrina4,Johnson Colin A.3ORCID,Mullegama Sureni V.5,McConkie-Rosell Allyn6,McDonald Marie6,Hansen Lars1,Vakhrushev Sergey Y.1,Schjoldager Katrine T.1ORCID,Clausen Henrik1ORCID,Worzfeld Thomas27,Joshi Hiren J.1ORCID,Halim Adnan1ORCID

Affiliation:

1. Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen N, Denmark

2. Faculty of Medicine, Institute of Pharmacology, University of Marburg, 35043 Marburg, Germany

3. Leeds Institute of Medical Research, University of Leeds, St James’ University Hospital, Leeds LS2 9JT, United Kingdom

4. Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds LS7 4SA, United Kingdom

5. GeneDx, Gaithersburg, MD 20877

6. Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710

7. Max-Planck-Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany

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.

Funder

Lundbeckfonden

China Scholarship Council

Sir Jules Thorn Charitable Trust

UKRI | Medical Research Council

British Heart Foundation

Deutsche Forschungsgemeinschaft

Danmarks Grundforskningsfond

Mizutani Foundation for Glycoscience

Villum Fonden

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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