Endoplasmic Reticulum Quality Control Is Involved in the Mechanism of Endoglin-Mediated Hereditary Haemorrhagic Telangiectasia

Autor: Nadia Akawi, Imen Ben-Rebeh, Shamma A. Al-Shamisi, Bassam R. Ali, Anne John, Reham M. Milhem, Mouza M. Al-Ameri, Nouf Ahmed Alshehhi, Lihadh Al-Gazali
Rok vydání: 2011
Předmět:
Models
Molecular
Mutant
Glycobiology
lcsh:Medicine
Telangiectases
Endoplasmic Reticulum
medicine.disease_cause
Biochemistry
Energy-Producing Processes
Molecular Cell Biology
Signaling in Cellular Processes
Missense mutation
Membrane Receptor Signaling
lcsh:Science
Genetics
Mutation
Multidisciplinary
Endoglin
Cellular Structures
Protein Transport
Autosomal Dominant
Cytochemistry
Telangiectasia
Hereditary Hemorrhagic
Membranes and Sorting
Immunocytochemistry
Subcellular Fractions
Research Article
Signal Transduction
Glycoside Hydrolases
Mutation
Missense
Receptors
Cell Surface
Biology
Molecular Genetics
Antigens
CD
Genetic Mutation
medicine
Humans
Glycoproteins
Organelles
Smad Signaling
Endoplasmic reticulum
lcsh:R
Cell Membrane
Proteins
Human Genetics
ACVRL1
Protein Structure
Tertiary
Subcellular Organelles
Membrane protein
Mutagenesis
Genetics of Disease
Cancer research
lcsh:Q
Mutant Proteins
HeLa Cells
Zdroj: PLoS ONE
PLoS ONE, Vol 6, Iss 10, p e26206 (2011)
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0026206
Popis: 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.
Databáze: OpenAIRE
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