Abstract
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant, vascular disorder that presents with telangiectases and arteriovenous malformations. HHT is a genetically heterogeneous disorder, involving mutations in endoglin (ENG; HHT1) and activin receptor-like kinase 1 (ACVRL1/ALK1; HHT2) genes that account for over 85% of all HHT patients. The current diagnosis of HHT patients remains at the clinical level, but many suspected patients do not have a clear HHT diagnosis or do not show pathogenic mutations in HHT genes. This situation has prompted the search for biomarkers to help in the early diagnosis of the disease. We have analyzed the plasma levels in HHT patients of selected micro-RNAs (miRNAs), small single-stranded RNAs that regulate gene expression at the transcriptional level by interacting with specific RNA targets. A total of 16 HHT1 and 17 HHT2 plasma samples from clinically confirmed patients and 16 controls were analyzed in this study. Total RNA was purified from plasma, and three selected miRNAs (miRNA-10a, miRNA-214, and miRNA-370), related to the pathobiology of cardiovascular diseases and potentially targeting ENG or ALK1, were measured by quantitative polymerase chain reaction. Compared with controls, levels of miRNA-370, whose putative target is ENG, were significantly downregulated in HHT1, but not in HHT2, whereas the levels of miRNA-10a, whose putative target is ALK1, were significantly upregulated in HHT2, but not in HHT1. In addition, the levels of miRNA-214, potentially targeting ENG and ALK1, did not change in either HHT1 or HHT2 patients versus control samples. While further studies are warranted, these results suggest that dysregulated plasma levels of miRNA-370 or miRNA-10a could help to identify undiagnosed HHT1 or HHT2 patients, respectively.
Highlights
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant, vascular disorder with a prevalence of approximately 1 in 8000 people worldwide [1,2]
HHT is genetically heterogeneous with heterozygous mutations in at least three known genes including endoglin (ENG) causing HHT1 [6], activin receptor-like kinase 1 (ACVRL1 or ALK1), causing HHT2 [7], and mothers against decapentaplegic homolog 4 (MADH4 or SMAD4) causing familial juvenile polyposis associated with HHT (JP/HT) [8]
In order to identify specific biomarkers of HHT, we searched for miRNAs involved in angiogenesis and vascular homeostasis and predicted to target ENG and/or ALK1 using three robust target prediction programs which use different algorithms: (i) microRNA [28]; (ii) Target Scan [29]; and (iii) MicroCosm [30]
Summary
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant, vascular disorder with a prevalence of approximately 1 in 8000 people worldwide [1,2]. The presence of pulmonary, hepatic, and cerebral AVMs in HHT patients suggests that they are at risk of life-threatening hemorrhage and complications involving shunting, leading to stroke, high-output cardiac failure, or brain abscess [3,4,5]. Mutations in the GDF2 gene, encoding bone morphogenetic protein 9 (BMP9), were described as the cause of an HHT-like syndrome [9]. All the genes mutated in HHT encode proteins that are involved in the signaling pathway of transforming growth factor beta (TGF-β)/bone morphogenetic protein (BMP). The auxiliary receptor endoglin associates with the signaling serine/threonine receptor ALK1 and both proteins are able to bind ligands like BMP9, leading to the phosphorylation and nuclear translocation of a Smad protein complex that includes Smad4 [12,13,14]. Because endothelial cells are functional targets of circulating BMP9, and predominantly express endoglin and ALK1, these are widely accepted as the target cells in HHT
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
