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Retention in the endoplasmic reticulum is the underlying mechanism of some hereditary haemorrhagic telangiectasia type 2 ALK1 missense mutations

Overview of attention for article published in Molecular and Cellular Biochemistry, November 2012
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Title
Retention in the endoplasmic reticulum is the underlying mechanism of some hereditary haemorrhagic telangiectasia type 2 ALK1 missense mutations
Published in
Molecular and Cellular Biochemistry, November 2012
DOI 10.1007/s11010-012-1496-3
Pubmed ID
Authors

Alistair N. Hume, Anne John, Nadia A. Akawi, Aydah M. Al-Awadhi, Sarah S. Al-Suwaidi, Lihadh Al-Gazali, Bassam R. Ali

Abstract

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterised by vascular dysplasia and increased bleeding that affect 1 in 5,000 people world-wide. Pathology is linked to mutations in genes encoding components of the heteromeric transforming growth factor-beta receptor (TGF-beta) and SMAD signalling pathway. Indeed HHT1 and HHT2 result from mutations in the genes encoding endoglin and activin-like kinase 1 (ALK1), TGF-beta receptor components. However, the fundamental cellular defects underlying HHT is poorly understood. Previously using confocal microscopy and N-glycosylation analysis, we found evidence that defective trafficking of endoglin from the endoplasmic reticulum (ER) to the plasma membrane is a mechanism underlying HHT1 in some patients. In this study, we used confocal microscopy to investigate whether a similar mechanism contributes to HHT2 pathology. To do this we expressed wild-type ALK1 and a number of HHT2 patient mutant variants as C-terminally tagged EGFP fusion proteins and tested their localisation in HeLa cells. We found that wild-type ALK1-EGFP was targeted predominantly to the plasma membrane, as evidenced by its colocalisation with the co-expressed HA-tagged endoglin. However, we found that in the majority of cases analysed the HHT2 patient mutant protein was retained within the ER as indicated by their colocalisation with the ER resident marker (calnexin) and lack of colocalisation with cell surface associated HA-endoglin. We conclude that defective trafficking and retention in the ER of mutant ALK1 protein is a possible mechanism of HHT2 in some patients.

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Mendeley readers

The data shown below were compiled from readership statistics for 8 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Belgium 1 13%
Unknown 7 88%

Demographic breakdown

Readers by professional status Count As %
Researcher 4 50%
Student > Ph. D. Student 2 25%
Student > Master 1 13%
Professor > Associate Professor 1 13%
Readers by discipline Count As %
Agricultural and Biological Sciences 5 63%
Medicine and Dentistry 2 25%
Biochemistry, Genetics and Molecular Biology 1 13%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 09 November 2012.
All research outputs
#7,702,884
of 12,325,396 outputs
Outputs from Molecular and Cellular Biochemistry
#933
of 1,550 outputs
Outputs of similar age
#72,127
of 132,246 outputs
Outputs of similar age from Molecular and Cellular Biochemistry
#10
of 27 outputs
Altmetric has tracked 12,325,396 research outputs across all sources so far. This one is in the 23rd percentile – i.e., 23% of other outputs scored the same or lower than it.
So far Altmetric has tracked 1,550 research outputs from this source. They receive a mean Attention Score of 3.6. This one is in the 33rd percentile – i.e., 33% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 132,246 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 33rd percentile – i.e., 33% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 27 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 59% of its contemporaries.