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

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.

SUBMITTER: Larsen ISB

PROVIDER: S-EPMC10214176 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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The SHDRA syndrome-associated gene <i>TMEM260</i> encodes a protein-specific O-mannosyltransferase.

Larsen Ida Signe Bohse ISB Povolo Lorenzo L Zhou Luping L Tian Weihua W Mygind Kasper Johansen KJ Hintze John J Jiang Chen C Hartill Verity V Prescott Katrina K Johnson Colin A CA Mullegama Sureni V SV McConkie-Rosell Allyn A McDonald Marie M Hansen Lars L Vakhrushev Sergey Y SY Schjoldager Katrine T KT Clausen Henrik H Worzfeld Thomas T Joshi Hiren J HJ Halim Adnan A

Proceedings of the National Academy of Sciences of the United States of America 20230515 21

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 ...[more]

PMID: 37186866

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Project description:The family of mammalian O-mannosyltransferases includes two enzymes, POMT1 and POMT2, which are thought to be essential for muscle and neural development. Similar to mammalian organisms, Drosophila has two O-mannosyltransferase genes, rotated abdomen (rt) and DmPOMT2, encoding proteins with high homology to their mammalian counterparts. The previously reported mutant phenotype of the rt gene includes a clockwise rotation of the abdomen and defects in embryonic muscle development. No mutants have been described so far for the DmPOMT2 locus. In this study, we determined that the mutation in the twisted (tw) locus, tw(1), corresponds to a DmPOMT2 mutant. The twisted alleles represent a complementation group of recessive mutations that, similar to the rt mutants, exhibit a clockwise abdomen rotation phenotype. Several tw alleles were isolated in the past; however, none of them was molecularly characterized. We used an expression rescue approach to confirm that tw locus represents DmPOMT2 gene. We found that the tw1 allele represents an amino acid substitution within the conserved PMT domain of DmPOMT2 (TW) protein. Immunostaining experiments revealed that the protein products of both rt and tw genes colocalize within Drosophila cells where they reside in the ER subcellular compartment. In situ hybridization analysis showed that both genes have essentially overlapping patterns of expression throughout most of embryogenesis (stages 8-17), while only the rt transcript is present at early embryonic stages (5 and 6), suggesting its maternal origin. Finally, we analyzed the genetic interactions between rt and tw using several mutant alleles, RNAi, and ectopic expression approaches. Our data suggest that the two Drosophila O-mannosyltransferase genes, rt and tw, have nonredundant functions within the same developmental cascade and that their activities are required simultaneously for possibly the same biochemical process. Our results establish the possibility of using Drosophila as a model system for studying molecular and genetic mechanisms of protein O-mannosylation during development.

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

Publications

The SHDRA syndrome-associated gene <i>TMEM260</i> encodes a protein-specific O-mannosyltransferase.

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Dataset Information

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

Publications

The SHDRA syndrome-associated gene &lt;i&gt;TMEM260&lt;/i&gt; encodes a protein-specific O-mannosyltransferase.

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OmicsDI is part of the ELIXIR infrastructure

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The SHDRA syndrome-associated gene <i>TMEM260</i> encodes a protein-specific O-mannosyltransferase.