Characterization of a mutation in the zona pellucida module of Endoglin that causes Hereditary Hemorrhagic Telangiectasia

Ruíz-Llorente, Lidia; Chiapparino, Elisa; Plumitallo, Sara; Danesino, Cesare; Bayrak-Toydemir, Pınar; Pagella, Fabio; Manfredi, Guido; Bernabeu, Carmelo; Jovine, Luca; Olivieri, Carla

doi:10.1016/j.gene.2019.02.016

Cited by 5 publications

(7 citation statements)

References 34 publications

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“…ENG comprises a short cytosolic tail, a single hydrophobic transmembrane domain, and a large extracellular region which contains an N-terminal orphan region (OR) and a C-terminal bipartite zona pellucida (ZP) module (15,16). Ruiz-Llorente et al (17) found that a novel mutation in exon 9 of the ENG gene (c.1145 G>A), which involves Cys382 residue of ENG (p.Cys382>Tyr) in its ZP module, downregulates ENG expression, and thus has a pathogenic role in this variant of HHT1. ENG is expressed as a homodimer linked by intermolecular disulfide bonds.…”

Section: Discussionmentioning

confidence: 99%

“…In our study, we found that a family pedigree of HHT with PAVMs and CAVMs was associated with a novel ENG gene mutation, c.1466del, which is located on the 12 th exon of the ENG gene and causes p.Gln489Argfs*2 mutations in the ZP module of ENG. Large numbers of mutant ENG proteins with affected ZP modules interfere with hydrophobic core packing, which explains the impaired expression and/or secretion of the corresponding mutants (17). STRUM software predicted that ENG proteins with p.Gln489Argfs*2 mutations would have increased hydrophilicity and decreased hydrophobicity.…”

Section: Discussionmentioning

confidence: 99%

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A novel endoglin mutation in a family with hereditary hemorrhagic telangiectasia: a case report

et al. 2021

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Hereditary hemorrhagic telangiectasis (HHT) is an autosomal dominant vascular disease, and approximately 80% of all HHT cases are caused by gene mutation. In this report, we analyzed the case of an 11-year-old girl who had intracranial bleeding when she was 7 years old. Her brain computed tomography (CT) scans and craniocerebral angiography results revealed that she had multiple cerebral arteriovenous malformations (CAVMs). Cardiac computed tomography angiography (CTA) revealed a pulmonary arteriovenous malformation (PAVM) located in a segment of the left lung. This patient's primary diagnosis was of CAVMs and PAVMs. Both cerebral vascular embolization therapy and interventional treatment for PAVMs were performed to treat these respective conditions. The operations were successful and the patient's prognosis was good. To confirm the patient's diagnosis and the cause of her conditions, peripheral blood was collected from her and her family for whole-exome sequencing (WES). Sanger sequencing was used to verify these results and STRUM software was used to predict the presence of mutant proteins. We found a new mutation of the endoglin (ENG) gene present in this family; this mutation is known as c.1466del (p.Gln489Argfs*2). The patient's mother was a carrier of this heterozygous mutation. STRUM software confirmed that the configuration of the ENG protein p.Gln489Argfs2 site changed with this mutation. We believe this c.1466del (p.Gln489Argfs*2) mutation affects ENG protein function, and the resultant ENG protein dysfunction leads to HHT. When a child has multiple vascular malformation, HHT should be considered as a primary diagnosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A novel endoglin mutation in a family with hereditary hemorrhagic telangiectasia: a case report

et al. 2021

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“…Western blot analysis was performed as described previously [71]. Immunodetection was carried out by probing the membrane with a mouse monoclonal antibody (mAb) against human endoglin (P4A4; Developmental Studies Hybridoma Bank, University of Iowa, Iowa City, IA, USA) or the V5 artificial epitope (Sigma-Aldrich, Saint Louis, MO, USA) overnight at 4 °C, followed by incubation with the proper horseradish peroxidase-conjugated secondary antibody.…”

Section: Methodsmentioning

confidence: 99%

MMP-12, Secreted by Pro-Inflammatory Macrophages, Targets Endoglin in Human Macrophages and Endothelial Cells

Aristorena

Gallardo-Vara

Vicen

et al. 2019

IJMS

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Upon inflammation, monocyte-derived macrophages (MΦ) infiltrate blood vessels to regulate several processes involved in vascular pathophysiology. However, little is known about the mediators involved. Macrophage polarization is crucial for a fast and efficient initial response (GM-MΦ) and a good resolution (M-MΦ) of the inflammatory process. The functional activity of polarized MΦ is exerted mainly through their secretome, which can target other cell types, including endothelial cells. Endoglin (CD105) is a cell surface receptor expressed by endothelial cells and MΦ that is markedly upregulated in inflammation and critically involved in angiogenesis. In addition, a soluble form of endoglin with anti-angiogenic activity has been described in inflammation-associated pathologies. The aim of this work was to identify components of the MΦ secretome involved in the shedding of soluble endoglin. We find that the GM-MΦ secretome contains metalloprotease 12 (MMP-12), a GM-MΦ specific marker that may account for the anti-angiogenic activity of the GM-MΦ secretome. Cell surface endoglin is present in both GM-MΦ and M-MΦ, but soluble endoglin is only detected in GM-MΦ culture supernatants. Moreover, MMP-12 is responsible for the shedding of soluble endoglin in vitro and in vivo by targeting membrane-bound endoglin in both MΦ and endothelial cells. These data demonstrate a direct correlation between GM-MΦ polarization, MMP-12, and soluble endoglin expression and function. By targeting endothelial cells, MMP-12 may represent a novel mediator involved in vascular homeostasis.

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“…Endoglin promotes angiogenesis by activating pathways that promote proliferation and suppress apoptosis in the endothelium 67 . Some polymorphisms of endoglin are associated with an increased risk of cardiovascular damage, 68 and human mutations in endoglin contribute to HHT, characterized by arteriovenous malformations 69,70 . The role of endoglin in this disease is thought to be restricted to its function in veins and capillaries, but not the arteries, 71 and that endothelial endoglin normally prevents aberrantly high VEGF expression that helps cause these malformations and the subsequent impact on heart function 72 …”

Section: Tgf‐β Superfamily Co‐receptors and Their Role In Cancermentioning

confidence: 99%

TGF‐β superfamily co‐receptors in cancer

Pawlak

Blobe

2021

Developmental Dynamics

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Transforming growth factor‐β (TGF‐β) superfamily signaling via their cognate receptors is frequently modified by TGF‐β superfamily co‐receptors. Signaling through SMAD‐mediated pathways may be enhanced or depressed depending on the specific co‐receptor and cell context. This dynamic effect on signaling is further modified by the release of many of the co‐receptors from the membrane to generate soluble forms that are often antagonistic to the membrane‐bound receptors. The co‐receptors discussed here include TβRIII (betaglycan), endoglin, BAMBI, CD109, SCUBE proteins, neuropilins, Cripto‐1, MuSK, and RGMs. Dysregulation of these co‐receptors can lead to altered TGF‐β superfamily signaling that contributes to the pathophysiology of many cancers through regulation of growth, metastatic potential, and the tumor microenvironment. Here we describe the role of several TGF‐β superfamily co‐receptors on TGF‐β superfamily signaling and the impact on cellular and physiological functions with a particular focus on cancer, including a discussion on recent pharmacological advances and potential clinical applications targeting these co‐receptors.

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Characterization of a mutation in the zona pellucida module of Endoglin that causes Hereditary Hemorrhagic Telangiectasia

Abstract: El artículo seleccionado no se encuentra disponible por ahora a texto completo por no haber sido facilitado todavía por el investigador a cargo del archivo del mismo.

Cited by 5 publications

References 34 publications

A novel endoglin mutation in a family with hereditary hemorrhagic telangiectasia: a case report

A novel endoglin mutation in a family with hereditary hemorrhagic telangiectasia: a case report

MMP-12, Secreted by Pro-Inflammatory Macrophages, Targets Endoglin in Human Macrophages and Endothelial Cells

TGF‐β superfamily co‐receptors in cancer

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