Abstract
Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant genetic condition affecting the vascular system and is characterised by epistaxis, arteriovenous malformations and mucocutaneous and gastrointestinal telangiectases. This disorder affects approximately 1 in 8,000 people worldwide. Significant morbidity is associated with this condition in affected individuals, and anaemia can be a consequence of repeated haemorrhages from telangiectasia in the gut and nose. In the majority of the cases reported, the condition is caused by mutations in either ACVRL1 or endoglin genes, which encode components of the TGF-beta signalling pathway. Numerous missense mutations in endoglin have been reported as causative defects for HHT but the exact underlying cellular mechanisms caused by these mutations have not been fully established despite data supporting a role for the endoplasmic reticulum (ER) quality control machinery. For this reason, we examined the subcellular trafficking of twenty-five endoglin disease-causing missense mutations. The mutant proteins were expressed in HeLa and HEK293 cell lines, and their subcellular localizations were established by confocal fluorescence microscopy alongside the analysis of their N-glycosylation profiles. ER quality control was found to be responsible in eight (L32R, V49F, C53R, V125D, A160D, P165L, I271N and A308D) out of eleven mutants located on the orphan extracellular domain in addition to two (C363Y and C382W) out of thirteen mutants in the Zona Pellucida (ZP) domain. In addition, a single intracellular domain missense mutant was examined and found to traffic predominantly to the plasma membrane. These findings support the notion of the involvement of the ER's quality control in the mechanism of a significant number, but not all, missense endoglin mutants found in HHT type 1 patients. Other mechanisms including loss of interactions with signalling partners as well as adverse effects on functional residues are likely to be the cause of the mutant proteins' loss of function.
Highlights
Hereditary hemorrhagic telangiectasia or Osler-Rendu-Weber syndrome is a genetically heterogeneous autosomal dominant vascular disorder characterized by multiorgan vascular dysplasias, recurrent epistaxis and mucocutaneous telangiectasia [1,2,3]
We examine the trafficking of a significant number of missense mutations in endoglin that are found in HHT1 patients and demonstrate that retention in the endoplasmic reticulum (ER) by the ER quality control system significantly contributes to the cellular mechanism of this condition
Structural modelling of the extracellular domains of the human endoglin protein revealed two major domains, an orphan Nterminal domain that comprise residues Glu26-Ile359 and Zona Pellucida (ZP) domain that comprises residues Gln360-Gly586 [19]
Summary
Hereditary hemorrhagic telangiectasia or Osler-Rendu-Weber syndrome is a genetically heterogeneous autosomal dominant vascular disorder characterized by multiorgan vascular dysplasias, recurrent epistaxis and mucocutaneous telangiectasia [1,2,3]. HHT can be classified into at least two types; type 1 (HHT1; OMIM 187300) is caused by mutations in Endoglin (ENG) gene and type 2 (HHT2; OMIM 600376) is caused by mutations in activin receptor-like kinase 1 (ACVRL1) gene [4], [10], [11]. Mutations in both genes account for nearly 85% of all HHT cases while the remaining cases are caused by mutations in SMAD4 or other yet unknown genes [11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
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 call
