Mutations in NOTCH1 Cause Adams-Oliver Syndrome

Stittrich, Anna Barbara; Lehman, Anna; Bodian, Dale L.; Ashworth, Justin; Zong, Zheyuan; Li, Hong; Lam, Patricia; Khromykh, Alina; Iyer, Ramaswamy K.; Vockley, Joseph G.; Baveja, Rajiv; Silva, Ermelinda Santos; Dixon, Joanne; Leon, Eyby; Solomon, Benjamin D.; Glusman, Gustavo; Niederhuber, John E.; Roach, Jared C.; Patel, Millan S.

doi:10.1016/j.ajhg.2014.07.011

Cited by 159 publications

(152 citation statements)

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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: 51%

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

confidence: 51%

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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“…The control pedigrees were originally ascertained on a variety of nonpsychiatric diseases, including a large pedigree segregating a monogenic form of cardiomyopathy (39), 10 pedigrees with Adams-Oliver syndrome (40,41), 3 pedigrees with Fanconi anemia, and other ongoing studies. Individuals in the control pedigrees are likely to have a rate of BD comparable to that in the broader population (∼1-2%).…”

Section: Methodsmentioning

confidence: 99%

Rare variants in neuronal excitability genes influence risk for bipolar disorder

Ament

Szelinger

Glusman

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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We sequenced the genomes of 200 individuals from 41 families multiply affected with bipolar disorder (BD) to identify contributions of rare variants to genetic risk. We initially focused on 3,087 candidate genes with known synaptic functions or prior evidence from genomewide association studies. BD pedigrees had an increased burden of rare variants in genes encoding neuronal ion channels, including subunits of GABA A receptors and voltage-gated calcium channels. Four uncommon coding and regulatory variants also showed significant association, including a missense variant in GABRA6. Targeted sequencing of 26 of these candidate genes in an additional 3,014 cases and 1,717 controls confirmed rare variant associations in ANK3, CACNA1B, CACNA1C, CACNA1D, CACNG2, CAMK2A, and NGF. Variants in promoters and 5′ and 3′ UTRs contributed more strongly than coding variants to risk for BD, both in pedigrees and in the case-control cohort. The genes and pathways identified in this study regulate diverse aspects of neuronal excitability. We conclude that rare variants in neuronal excitability genes contribute to risk for BD. by episodes of mania and depression (1). Episodes of mania are marked by elevated or alternatively irritable mood, grandiosity, racing thoughts, rapid speech, diminished need for sleep, and risk-taking behavior. Depression includes sadness, low energy and motivation, decreased ability to experience pleasure, insomnia, and appetite changes. Psychosis with hallucinations and delusions can occur in either state. BD affects 1-2% of the US population, and if untreated, up to 15% of patients die from suicide. Twin and family studies suggest that heritable causes explain 60-80% of lifetime risk for BD (2), with an approximate eightfold relative risk in the siblings of BD probands (3). Several common genetic markers have shown significant and replicable associations in genome-wide association studies (GWASs), including a region near a voltage-gated calcium channel, CACNA1C, and another near a synaptic scaffolding gene, ANK3 (4). Additive effects of common loci detectable on commercially available genomic arrays may be used to predict about 25% of the risk for BD (5), but typically the function and exact location of the causative variants linked to these loci is unknown.Rare variants may explain additional risk for BD. It is possible that one or a few rare variants of large effect dramatically increase disease risk, resulting in an inheritance model resembling monogenic inheritance in a given family. However, four exomesequencing and whole-genome sequencing (WGS) studies of BD pedigrees have detected few, if any, plausible variants of large effect (6-9). An alternative oligogenic model posits that different combinations of several uncommon or rare variants of moderate effect cluster in affected individuals and collectively cause disease.To test the hypothesis that rare variants contribute to risk for BD, we sequenced the genomes of 200 individuals from 41 multiply affected BD pedigrees of European ancestry. We seque...

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“…In the context of Notch, this cortical signaling pathway may explain why human mutations in the Notch receptor family have demonstrated vascular defects and barrier dysfunction in human diseases such as CADASIL, Adams-Oliver Syndrome, and Alagille syndrome 26–28 , and why inhibition of Notch signaling to treat tumors appears to trigger edema 29 . Identifying ways to isolate the cortical from transcriptional pathway of Notch may provide new opportunities to control these devastating complications.…”

mentioning

confidence: 99%

A non-canonical Notch complex regulates adherens junctions and vascular barrier function

Polacheck

Kutys

Yang

et al. 2017

Nature

277

315

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The vascular barrier that separates blood from tissues is actively regulated by the endothelium and is essential for transport, inflammation, and hemostasis1. Hemodynamic shear stress plays a critical role in maintaining endothelial barrier function2, but how this occurs remains unknown. Here, using an engineered organotypic model of perfused microvessels and confirming in mouse models, we identify that activation of the Notch1 transmembrane receptor directly regulates vascular barrier function through a non-canonical, transcription independent signaling mechanism that drives adherens junction assembly. Shear stress triggers Dll4-dependent proteolytic activation of Notch1 to reveal the Notch1 transmembrane domain – the key domain that mediates barrier establishment. Expression of the Notch1 transmembrane domain is sufficient to rescue Notch1 knockout-induced defects in barrier function, and does so by catalyzing the formation of a novel receptor complex in the plasma membrane consisting of VE-cadherin, the transmembrane protein tyrosine phosphatase LAR, and the Rac1 GEF Trio. This complex activates Rac1 to drive adherens junction assembly and establish barrier function. Canonical Notch transcriptional signaling is highly conserved throughout metazoans and is required for many processes in vascular development, including arterial-venous differentiation3, angiogenesis4, and remodeling5; here, we establish the existence of a previously unappreciated non-canonical cortical signaling pathway for Notch1 that regulates vascular barrier function, and thus provide a mechanism by which a single receptor might link transcriptional programs with adhesive and cytoskeletal remodeling.

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Mutations in NOTCH1 Cause Adams-Oliver Syndrome

Cited by 159 publications

References 50 publications

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

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

Rare variants in neuronal excitability genes influence risk for bipolar disorder

A non-canonical Notch complex regulates adherens junctions and vascular barrier function

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