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A Christianson syndrome-linked deletion mutation (∆287ES288) in SLC9A6 disrupts recycling endosomal function and elicits neurodegeneration and cell death

Overview of attention for article published in Molecular Neurodegeneration, September 2016
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  • In the top 25% of all research outputs scored by Altmetric
  • Good Attention Score compared to outputs of the same age (73rd percentile)

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1 Wikipedia page

Citations

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14 Dimensions

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Title
A Christianson syndrome-linked deletion mutation (∆287ES288) in SLC9A6 disrupts recycling endosomal function and elicits neurodegeneration and cell death
Published in
Molecular Neurodegeneration, September 2016
DOI 10.1186/s13024-016-0129-9
Pubmed ID
Authors

Alina Ilie, Andy Y. L. Gao, Jonathan Reid, Annie Boucher, Cassandra McEwan, Hervé Barrière, Gergely L. Lukacs, R. Anne McKinney, John Orlowski

Abstract

Christianson Syndrome, a recently identified X-linked neurodevelopmental disorder, is caused by mutations in the human gene SLC9A6 encoding the recycling endosomal alkali cation/proton exchanger NHE6. The patients have pronounced limitations in cognitive ability, motor skills and adaptive behaviour. However, the mechanistic basis for this disorder is poorly understood as few of the more than 20 mutations identified thus far have been studied in detail. Here, we examined the molecular and cellular consequences of a 6 base-pair deletion of amino acids Glu(287) and Ser(288) (∆ES) in the predicted seventh transmembrane helix of human NHE6 expressed in established cell lines (CHO/AP-1, HeLa and neuroblastoma SH-SY5Y) and primary cultures of mouse hippocampal neurons by measuring levels of protein expression, stability, membrane trafficking, endosomal function and cell viability. In the cell lines, immunoblot analyses showed that the nascent mutant protein was properly synthesized and assembled as a homodimer, but its oligosaccharide maturation and half-life were markedly reduced compared to wild-type (WT) and correlated with enhanced ubiquitination leading to both proteasomal and lysosomal degradation. Despite this instability, a measurable fraction of the transporter was correctly sorted to the plasma membrane. However, the rates of clathrin-mediated endocytosis of the ∆ES mutant as well as uptake of companion vesicular cargo, such as the ligand-bound transferrin receptor, were significantly reduced and correlated with excessive endosomal acidification. Notably, ectopic expression of ∆ES but not WT induced apoptosis when examined in AP-1 cells. Similarly, in transfected primary cultures of mouse hippocampal neurons, membrane trafficking of the ∆ES mutant was impaired and elicited marked reductions in total dendritic length, area and arborization, and triggered apoptotic cell death. These results suggest that loss-of-function mutations in NHE6 disrupt recycling endosomal function and trafficking of cargo which ultimately leads to neuronal degeneration and cell death in Christianson Syndrome.

Twitter Demographics

The data shown below were collected from the profiles of 3 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 22 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Colombia 1 5%
Belgium 1 5%
Unknown 20 91%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 5 23%
Researcher 3 14%
Student > Bachelor 3 14%
Other 3 14%
Professor 2 9%
Other 4 18%
Unknown 2 9%
Readers by discipline Count As %
Medicine and Dentistry 6 27%
Agricultural and Biological Sciences 6 27%
Biochemistry, Genetics and Molecular Biology 4 18%
Neuroscience 2 9%
Engineering 1 5%
Other 0 0%
Unknown 3 14%

Attention Score in Context

This research output has an Altmetric Attention Score of 6. 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 11 August 2017.
All research outputs
#4,557,055
of 18,394,878 outputs
Outputs from Molecular Neurodegeneration
#416
of 714 outputs
Outputs of similar age
#72,508
of 272,686 outputs
Outputs of similar age from Molecular Neurodegeneration
#2
of 2 outputs
Altmetric has tracked 18,394,878 research outputs across all sources so far. Compared to these this one has done well and is in the 75th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 714 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 10.8. This one is in the 41st percentile – i.e., 41% 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 272,686 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 73% of its contemporaries.
We're also able to compare this research output to 2 others from the same source and published within six weeks on either side of this one.