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  4. In-depth analysis of hyaline fibromatosis syndrome frameshift mutations at the same site reveal the necessity of personalized therapy
 
research article

In-depth analysis of hyaline fibromatosis syndrome frameshift mutations at the same site reveal the necessity of personalized therapy

Yan, Shixu E.
•
Lemmin, Thomas  
•
Salvi, Suzanne
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2013
Human mutation

Hyaline fibromatosis syndrome is an autosomal recessive disease caused by mutations in ANTXR2, a gene involved in extracellular matrix homeostasis. Sixty percent of patients carry frameshift mutations at a mutational hotspot in exon 13. We show in patient cells that these mutations lead to low ANTXR2 mRNA and undetectable protein levels. Ectopic expression of the proteins encoded by the mutated genes reveals that a two base insertion leads to the synthesis of a protein that is rapidly targeted to the ER-associated degradation pathway due to the modified structure of the cytosolic tail, which instead of being hydrophilic and highly disordered as in wild type ANTXR2, is folded and exposes hydrophobic patches. In contrast, one base insertion leads to a truncated protein that properly localizes to the plasma membrane and retains partial function. We next show that targeting the nonsense mediated mRNA decay pathway in patient cells leads to a rescue of ANTXR2 protein in patients carrying one base insertion but not in those carrying two base insertions. This study highlights the importance of in-depth analysis of the molecular consequences of specific patient mutations, which even when they occur at the same site can have drastically different consequences.

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Type
research article
DOI
10.1002/humu.22324
Web of Science ID

WOS:000320551300011

Author(s)
Yan, Shixu E.
•
Lemmin, Thomas  
•
Salvi, Suzanne
•
Lausch, Ekkehart
•
Superti-Furga, Andrea
•
Rokicki, Dariusz
•
Dal Peraro, Matteo  
•
van der Goot, Gisou  
Date Issued

2013

Publisher

Wiley-Blackwell

Published in
Human mutation
Volume

34

Issue

7

Start page

1005

End page

17

Subjects

hyaline fibromatosis syndrome

•

ANTXR2

•

NMD

•

degradation

Peer reviewed

REVIEWED

Written at

EPFL

EPFL units
VDG  
UPDALPE  
Available on Infoscience
July 5, 2013
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/93214
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