Adams–Oliver syndrome caused by mutations of  the <i>EOGT</i> gene

Schroder, Kim; Duman, Duygu; Tekin, Mustafa; Schanze, Denny; Sukalo, Maja; Meester, Josephina; Wuyts, Wim; Zenker, Martin

doi:10.1002/ajmg.a.61313

Cited by 18 publications

(13 citation statements)

References 16 publications

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“…Several congenital diseases inhibit the synthesis or extension of O-glycans that regulate Notch signaling and may induce immune cell defects. Mutations in EOGT cause Adams Oliver syndrome or EOGT-CDG ( 15 ) and autosomal dominant mutations in POFUT1 cause Dowling Degos Disease 2 (DDD2) or POFUT1-CDG ( 39 ). Here we show that the generation of certain lymphoid and myeloid subsets in bone marrow, thymus and spleen were perturbed in mice lacking Eogt .…”

Section: Discussionmentioning

confidence: 99%

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Synergistic regulation of Notch signaling by different O-glycans promotes hematopoiesis

Tanwar

Stanley

2022

Preprint

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Glycosylation of Notch receptors by O-fucose glycans regulates Notch ligand binding and Notch signaling during hematopoiesis. However, roles in hematopoiesis for other O-glycans that modify Notch receptors have not been determined. Here we show that the EGF domain specific GlcNAc transferase EOGT is required in mice for the optimal production of lymphoid and myeloid cells. The phenotype of Eogt null mice was largely cell-autonomous, and Notch target gene expression was reduced in T cell progenitors. Moreover, EOGT supported residual Notch signaling following conditional deletion of Pofut1 in hematopoietic stem cells (HSC). Eogt:Pofut1 double mutant HSC had more severe defects in bone marrow, and in T and B cell development in thymus and spleen, compared to deletion of Pofut1 alone. The combined results show that EOGT and O-GlcNAc glycans are required for optimal hematopoiesis and T and B cell development, and that they act synergistically with POFUT1 and O-fucose glycans to promote Notch signaling in lymphoid and myeloid differentiation.

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Section: Discussionmentioning

confidence: 99%

“…DLL1-induced NOTCH2 signaling is essential for the generation of marginal zone B cells (MZ-B) in the spleen ( 13, 14 ). O-fucose glycans extended by ( 15 )LFNG and MFNG together promote the formation of MZ-B cells ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

Synergistic regulation of Notch signaling by different O-glycans promotes hematopoiesis

Tanwar

Stanley

2022

Preprint

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“…This protein is present in both the nucleus and the cytosol. Its defect has been labelled as Adams-Oliver syndrome 4 ( 15 ).…”

Section: Cytosolic Cdgmentioning

confidence: 99%

Congenital disorders of glycosylation (CDG), a multigenetic disease family with multiple subcellular locations

Jaeken

2020

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“…EOGT mutations inhibit the NOTCH1 signalling pathway and cause several congenital developmental disorders, such as Adams-Oliver syndrome [6]. Activation of the NOTCH1 signalling pathway promotes pancreatic cancer cellproliferation, stemnessand chemotherapy resistance [7,8].…”

Section: Introductionmentioning

confidence: 99%

SHCBP1 interacting with EOGT enhanced O-GlcNAcylation of NOTCH1 and promoted the development of pancreatic cancer .

Yang

Zhan

et al. 2020

Preprint

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Background: Pancreatic cancer(PDAC) remains one of the most lethal cancers worldwide, The accumulation of many abnormal epigenetic abnormalities contribute to the fatal prognosis of PDAC,While available studies are still limited. Many studies have confirmed that the Shc SH2-domain binding protein 1(SHCBP1) plays as proto-oncogene in cancers. However, whether SHCBP1 plays a role in pancreatic cancer oncogenesis is still unknown.EGF domain-specific O-linked GlcNActransferase (EOGT) acts as a key participant in the O-GlcNAcylation of NOTCH1. EOGT mutations inhibit the NOTCH1 signalling pathway and cause several congenital developmental disorders, However, the role of EOGT in malignancies has not been reported.Methods:SHCBP1 and EOGT were identified as proto-oncogenes in PDAC by High-throughput sequencing and Cox regression analysis,and validated by Internal and External cohort and public databases. The function of SHCBP1 and EOGT was determined in vitro and in vivo, The underlying mechanism was investigated by Western blot,Immunofluorescence（IF），Co-immunoprecipitation (Co-IP), Chromatin immunoprecipitation (ChIP)，and luciferase analyses.Results: The expression of EOGT and SHCBP1 was significantly elevated and correlated with worse prognosis in PDAC patients. In vitro, SHCBP1 overexpression promoted pancreatic cancer cell proliferation,migration and invasion, while knocking down SHCBP1 and EOGT inhibited these malignant processes. In vivo data showed that SHCBP1 overexpression promoted xenograft growth and lung metastasis and shortened survival in mice,whereas knocking down either EOGT or SHCBP1 expression suppressed xenograft growth and metastasis and prolonged survival. Morever，EOGT and SHCBP1 enhance the O-GlcNAcylation of NOTCH1, subsequently promoting the nuclear localization of the Notch intracellular domain (NICD) and inhibiting the transcription of E-cadherin and P21 in pancreatic cancer cells.Conclusion:All in all，This research revealed that SHCBP1 and EOGT act as proto-oncogenes in PDAC by enhancing the O-GlcNAcylation of NOTCH1，Which provides a new field of vision for new therapeutic targets for pancreatic cancer.

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Adams–Oliver syndrome caused by mutations of the EOGT gene

Cited by 18 publications

References 16 publications

Synergistic regulation of Notch signaling by different O-glycans promotes hematopoiesis

Synergistic regulation of Notch signaling by different O-glycans promotes hematopoiesis

Congenital disorders of glycosylation (CDG), a multigenetic disease family with multiple subcellular locations

SHCBP1 interacting with EOGT enhanced O-GlcNAcylation of NOTCH1 and promoted the development of pancreatic cancer .

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