RBPJ Mutations Identified in Two Families Affected by Adams-Oliver Syndrome

Hassed, Susan J.; Wiley, Graham B.; Wang, Shaofeng; Lee, Ji Yun; Li, Shibo; Xu, Weihong; Zhao, Zhizhuang Joe; Mulvihill, John J.; Robertson, James A.; Warner, James; Gaffney, Patrick M.

doi:10.1016/j.ajhg.2012.07.005

Cited by 106 publications

(95 citation statements)

References 26 publications

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“…Consistent with our data, it is reported that mutations in human RBPJ may lead to skin telangiectasias, which are small vascular malformations directly under the surface of the skin (Hassed et al, 2012). Currently, known genetic lesions account for very few human AVM cases (Young and Yang, 2004), and it is of upmost clinical interest to describe and investigate novel molecular mechanisms of AVM formation and progression.…”

Section: Deletion Of Endothelial Rbpj Results In Vascular Abnormalitisupporting

confidence: 73%

“…Human patients with mutations in RBPJ are affected by AdamsOliver syndrome and may present with cardiovascular anomalies and/or skin telangiectasias (Hassed et al, 2012). Given that the expression of a Notch gain-of-function mutation in the endothelium just after birth reprograms the molecular identity of arterial and venous ECs and leads to abnormal AV shunts in immature mouse brains, and that loss of endothelial Notch during embryogenesis also reprograms the AV identity of ECs and results in AV anastomoses, we tested whether Notch signaling is required in postnatal endothelium to maintain AV organization and AV marker expression.…”

Section: Introductionmentioning

confidence: 99%

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Deletion of Rbpj from postnatal endothelium leads to abnormal arteriovenous shunting in mice

et al. 2014

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Arteriovenous malformations (AVMs) are tortuous vessels characterized by arteriovenous (AV) shunts, which displace capillaries and shunt blood directly from artery to vein. Notch signaling regulates embryonic AV specification by promoting arterial, as opposed to venous, endothelial cell (EC) fate. To understand the essential role of endothelial Notch signaling in postnatal AV organization, we used inducible Cre-loxP recombination to delete Rbpj, a mediator of canonical Notch signaling, from postnatal ECs in mice. Deletion of endothelial Rbpj from birth resulted in features of AVMs by P14, including abnormal AV shunting and tortuous vessels in the brain, intestine and heart. We further analyzed brain AVMs, as they pose particular health risks. Consistent with AVM pathology, we found cerebral hemorrhage, hypoxia and necrosis, and neurological deficits. AV shunts originated from capillaries (and possibly venules), with the earliest detectable morphological abnormalities in AV connections by P8. Prior to AV shunt formation, alterations in EC gene expression were detected, including decreased Efnb2 and increased Pai1, which encodes a downstream effector of TGFβ signaling. After AV shunts had formed, whole-mount immunostaining showed decreased Efnb2 and increased Ephb4 expression within AV shunts, suggesting that ECs were reprogrammed from arterial to venous identity. Deletion of Rbpj from adult ECs led to tortuosities in gastrointestinal, uterine and skin vascular beds, but had mild effects in the brain. Our results demonstrate a temporal requirement for Rbpj in postnatal ECs to maintain proper artery, capillary and vein organization and to prevent abnormal AV shunting and AVM pathogenesis.

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Section: Deletion Of Endothelial Rbpj Results In Vascular Abnormalitisupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Deletion of Rbpj from postnatal endothelium leads to abnormal arteriovenous shunting in mice

et al. 2014

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“…Moreover, mutations in human EOGT have been reported in an autosomal recessive form of a human disease called AdamsOliver syndrome (55,56). Notably, mutations in several Notch pathway components cause an autosomal dominant form of the same disease (39,40,(57)(58)(59). Together, these reports provide strong evidence that O-GlcNAcylation might modulate Notch signaling.…”

Section: Eics Of O-glucose Sites Represented By Peptides Also Containsupporting

confidence: 50%

Mapping Sites of O-Glycosylation and Fringe Elongation on Drosophila Notch

Harvey

Rana

Moss

et al. 2016

Journal of Biological Chemistry

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Glycosylation of the Notch receptor is essential for its activity and serves as an important modulator of signaling. Three major forms of O-glycosylation are predicted to occur at consensus sites within the epidermal growth factor-like repeats in the extracellular domain of the receptor: O-fucosylation, O-glucosylation, and O-GlcNAcylation. We have performed comprehensive mass spectral analyses of these three types of O-glycosylation on Drosophila Notch produced in S2 cells and identified peptides containing all 22 predicted O-fucose sites, all 18 predicted O-glucose sites, and all 18 putative O-GlcNAc sites. Using semiquantitative mass spectral methods, we have evaluated the occupancy and relative amounts of glycans at each site. The majority of the O-fucose sites were modified to high stoichiometries. Upon expression of the ␤3-N-acetylglucosaminyltransferase Fringe with Notch, we observed varying degrees of elongation beyond O-fucose monosaccharide, indicating that Fringe preferentially modifies certain sites more than others. Rumi modified O-glucose sites to high stoichiometries, although elongation of the O-glucose was site-specific. Although the current putative consensus sequence for O-GlcNAcylation predicts 18 O-GlcNAc sites on Notch, we only observed apparent O-GlcNAc modification at five sites. In addition, we performed mass spectral analysis on endogenous Notch purified from Drosophila embryos and found that the glycosylation states were similar to those found on Notch from S2 cells. These data provide foundational information for future studies investigating the mechanisms of how O-glycosylation regulates Notch activity.

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“…AOS can be caused also by dominant mutations in RBPJ (MIM 147183), a transcriptional regulator of the NOTCH signaling pathway, further demonstrating the genetic heterogeneity of the phenotype. 5 As some features of AOS are consistent with vascular disruption pathogenesis, 2 it is yet unclear how disrupted Cdc42/Rac1 or NOTCH signaling intersects in the pathogenesis of AOS. Identification of additional genes implicated in AOS might elucidate common molecular pathways leading to this disease.…”

Section: Introductionmentioning

confidence: 99%

“…3,4 It is noteworthy that F-actin staining in our EOGT mutant fibroblasts showed apparently intact cell cytoskeleton and morphology. There is growing evidence that the AOS phenotype might be mediated through the NOTCH signaling pathway: AOS-causing RBPJ mutations are assumed to effect NOTCH signaling, 5 and drosophila Notch ligands Delta and Serrate, as well as mammalian Notch1 are O-GlcNAc-modified by Eogt. 8,11 Moreover, heterozygosity for either Notch or for several members of the canonical Notch signaling pathway suppresses wing blistering formation caused by Eogt knockdown in drosophila.…”

mentioning

confidence: 99%

Autosomal recessive Adams–Oliver syndrome caused by homozygous mutation in EOGT, encoding an EGF domain-specific O-GlcNAc transferase

et al. 2013

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Autosomal recessive Adams-Oliver syndrome was diagnosed in three remotely related Bedouin consanguineous families. Genome-wide linkage analysis ruled out association with known Adams-Oliver syndrome genes, identifying a singlehomozygosity B1.8-Mb novel locus common to affected individuals (LOD score 3.37). Whole-exome sequencing followed by Sanger sequencing identified only a single mutation within this locus, shared by all affected individuals and found in patients from five additional apparently unrelated Bedouin families: a 1-bp deletion mutation in a predicted alternative splice variant of EOGT, leading to a putative truncated protein. RT-PCR demonstrated that the EOGT-predicted alternative splice variant is ubiquitously expressed. EOGT encodes EGF-domain-specific O-linked N-acetylglucosamine transferase, responsible for extracellular O-GlcNAcylation of epidermal growth factor-like domain-containing proteins, and is essential for epithelial cell-matrix interactions. F-actin staining in diseased fibroblasts showed apparently intact cell cytoskeleton and morphology, suggesting the EOGT mutation acts not through perturbation of cytoskeleton but through other mechanisms yet to be elucidated.

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RBPJ Mutations Identified in Two Families Affected by Adams-Oliver Syndrome

Cited by 106 publications

References 26 publications

Deletion of Rbpj from postnatal endothelium leads to abnormal arteriovenous shunting in mice

Deletion of Rbpj from postnatal endothelium leads to abnormal arteriovenous shunting in mice

Mapping Sites of O-Glycosylation and Fringe Elongation on Drosophila Notch

Autosomal recessive Adams–Oliver syndrome caused by homozygous mutation in EOGT, encoding an EGF domain-specific O-GlcNAc transferase

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