Expanding the phenotype of cardiovascular malformations in Adams–Oliver syndrome

Algaze, Claudia; Lowenthal, Alexander; Hudgins, Louanne; Tacy, Theresa A.; Tierney, Elif Seda Selamet

doi:10.1002/ajmg.a.35864

Cited by 19 publications

(13 citation statements)

References 31 publications

(34 reference statements)

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“…The physiological importance of EOGT was revealed in patients with Adams-Oliver syndrome (AOS), a rare congenital disorder characterized by aplasia cutis congenita and terminal transverse limb defects, often accompanied by cardiovascular malformations and brain anomalies (Algaze et al, 2013; Piazza et al, 2004). Although the pathogenesis of AOS is broad, it could arise from small-vessel vasculopathy (Piazza et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

O-GlcNAc on NOTCH1 EGF repeats regulates ligand-induced Notch signaling and vascular development in mammals

Sawaguchi

Varshney

Ogawa

et al. 2017

eLife

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The glycosyltransferase EOGT transfers O-GlcNAc to a consensus site in epidermal growth factor-like (EGF) repeats of a limited number of secreted and membrane proteins, including Notch receptors. In EOGT-deficient cells, the binding of DLL1 and DLL4, but not JAG1, canonical Notch ligands was reduced, and ligand-induced Notch signaling was impaired. Mutagenesis of O-GlcNAc sites on NOTCH1 also resulted in decreased binding of DLL4. EOGT functions were investigated in retinal angiogenesis that depends on Notch signaling. Global or endothelial cell-specific deletion of Eogt resulted in defective retinal angiogenesis, with a mild phenotype similar to that caused by reduced Notch signaling in retina. Combined deficiency of different Notch1 mutant alleles exacerbated the abnormalities in Eogt−/− retina, and Notch target gene expression was decreased in Eogt−/−endothelial cells. Thus, O-GlcNAc on EGF repeats of Notch receptors mediates ligand-induced Notch signaling required in endothelial cells for optimal vascular development.DOI: http://dx.doi.org/10.7554/eLife.24419.001

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Section: Introductionmentioning

confidence: 99%

O-GlcNAc on NOTCH1 EGF repeats regulates ligand-induced Notch signaling and vascular development in mammals

Sawaguchi

Varshney

Ogawa

et al. 2017

eLife

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“…Of these, DLL4 has an essential role in vascular development and angiogenesis, which places it as a prime candidate for AOS, due to the presence of cardiovascular features in AOS-affected individuals. 14,15 The study was approved by the appropriate institutional review board, and appropriate informed consents were obtained from human subjects. We performed targeted resequencing of DLL4 on 89 individuals by using HaloPlex Targeted Enrichment (Agilent Technologies) followed by sequencing on MiSeq (Illumina) with 150 bp paired-end reads.…”

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confidence: 99%

Heterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome

Meester

Southgate

Stittrich

et al. 2015

The American Journal of Human Genetics

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Adams-Oliver syndrome (AOS) is a rare developmental disorder characterized by the presence of aplasia cutis congenita (ACC) of the scalp vertex and terminal limb-reduction defects. Cardiovascular anomalies are also frequently observed. Mutations in five genes have been identified as a cause for AOS prior to this report. Mutations in EOGT and DOCK6 cause autosomal-recessive AOS, whereas mutations in ARHGAP31, RBPJ, and NOTCH1 lead to autosomal-dominant AOS. Because RBPJ, NOTCH1, and EOGT are involved in NOTCH signaling, we hypothesized that mutations in other genes involved in this pathway might also be implicated in AOS pathogenesis. Using a candidate-gene-based approach, we prioritized DLL4, a critical NOTCH ligand, due to its essential role in vascular development in the context of cardiovascular features in AOS-affected individuals. Targeted resequencing of the DLL4 gene with a custom enrichment panel in 89 independent families resulted in the identification of seven mutations. A defect in DLL4 was also detected in two families via whole-exome or genome sequencing. In total, nine heterozygous mutations in DLL4 were identified, including two nonsense and seven missense variants, the latter encompassing four mutations that replace or create cysteine residues, which are most likely critical for maintaining structural integrity of the protein. Affected individuals with DLL4 mutations present with variable clinical expression with no emerging genotype-phenotype correlations. Our findings demonstrate that DLL4 mutations are an additional cause of autosomal-dominant AOS or isolated ACC and provide further evidence for a key role of NOTCH signaling in the etiology of this disorder.

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“…These include ventricular septal defect, tetralogy of fallot, pulmonary atresia, pulmonary arterial hypertension. 8 Other less commonly described associations include brain anamolies such as polymicrogyria, encephaly, hydrocephaly, cerebral cortical dysplasia, or even acrania, spina bifida, spina occulta, accessory nipples and cryptorchidism.…”

Section: Discussionmentioning

confidence: 99%

Aplasia cutis congenita

et al. 2019

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Aplasia cutis congenita (ACC) is a rare condition in which there is congenital focal absence of skin with or without absence of underlying structures such as bone. Consanguinity may play a role. The cause of this condition is unclear and appears to be multifactorial; contributory factors may include teratogens, genes, trauma and compromised blood flow to the skin. Various expressions of Adams Oliver syndrome (AOS) have also been reported which is a rare autosomal dominant congenital disorder characterized by absence of skin and or underlying structure over scalp along with transverse limb defect. It was first described by Adam and Oliver in 1945.

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Expanding the phenotype of cardiovascular malformations in Adams–Oliver syndrome

Cited by 19 publications

References 31 publications

O-GlcNAc on NOTCH1 EGF repeats regulates ligand-induced Notch signaling and vascular development in mammals

O-GlcNAc on NOTCH1 EGF repeats regulates ligand-induced Notch signaling and vascular development in mammals

Heterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome

Aplasia cutis congenita

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