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

Publication ,  Journal Article
Larsen, ISB; Povolo, L; Zhou, L; Tian, W; Mygind, KJ; Hintze, J; Jiang, C; Hartill, V; Prescott, K; Johnson, CA; Mullegama, SV; McDonald, M ...
Published in: Proc Natl Acad Sci U S A
May 23, 2023

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.

Duke Scholars

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

May 23, 2023

Volume

120

Issue

21

Start / End Page

e2302584120

Location

United States

Related Subject Headings

  • Mannosyltransferases
  • Mannose
  • Mammals
  • Glycosylation
  • Animals
 

Citation

APA
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Larsen, I. S. B., Povolo, L., Zhou, L., Tian, W., Mygind, K. J., Hintze, J., … Halim, A. (2023). The SHDRA syndrome-associated gene TMEM260 encodes a protein-specific O-mannosyltransferase. Proc Natl Acad Sci U S A, 120(21), e2302584120. https://doi.org/10.1073/pnas.2302584120
Larsen, Ida Signe Bohse, Lorenzo Povolo, Luping Zhou, Weihua Tian, Kasper Johansen Mygind, John Hintze, Chen Jiang, et al. “The SHDRA syndrome-associated gene TMEM260 encodes a protein-specific O-mannosyltransferase.Proc Natl Acad Sci U S A 120, no. 21 (May 23, 2023): e2302584120. https://doi.org/10.1073/pnas.2302584120.
Larsen ISB, Povolo L, Zhou L, Tian W, Mygind KJ, Hintze J, et al. The SHDRA syndrome-associated gene TMEM260 encodes a protein-specific O-mannosyltransferase. Proc Natl Acad Sci U S A. 2023 May 23;120(21):e2302584120.
Larsen, Ida Signe Bohse, et al. “The SHDRA syndrome-associated gene TMEM260 encodes a protein-specific O-mannosyltransferase.Proc Natl Acad Sci U S A, vol. 120, no. 21, May 2023, p. e2302584120. Pubmed, doi:10.1073/pnas.2302584120.
Larsen ISB, Povolo L, Zhou L, Tian W, Mygind KJ, Hintze J, Jiang C, Hartill V, Prescott K, Johnson CA, Mullegama SV, McConkie-Rosell A, McDonald M, Hansen L, Vakhrushev SY, Schjoldager KT, Clausen H, Worzfeld T, Joshi HJ, Halim A. The SHDRA syndrome-associated gene TMEM260 encodes a protein-specific O-mannosyltransferase. Proc Natl Acad Sci U S A. 2023 May 23;120(21):e2302584120.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

May 23, 2023

Volume

120

Issue

21

Start / End Page

e2302584120

Location

United States

Related Subject Headings

  • Mannosyltransferases
  • Mannose
  • Mammals
  • Glycosylation
  • Animals