In-Depth Analysis of Hyaline Fibromatosis Syndrome Frameshift Mutations at the Same Site Reveal the Necessity of Personalized Therapy

ABSTRACT 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...

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Bibliographic Details
Published in:Human mutation 2013-07, Vol.34 (7), p.1005-1017
Main Authors: Yan, Shixu E., Lemmin, Thomas, Salvi, Suzanne, Lausch, Ekkehart, Superti-Furga, Andrea, Rokicki, Dariusz, Dal Peraro, Matteo, van der Goot, F. Gisou
Format: Article
Language:English
Subjects:
Amino Acid Sequence
ANTXR2
Cells, Cultured
degradation
Exons - genetics
Fibroblasts - metabolism
Frameshift Mutation
Genes
HeLa Cells
Humans
hyaline fibromatosis syndrome
Hyaline Fibromatosis Syndrome - genetics
Hyaline Fibromatosis Syndrome - therapy
Infant
Kinases
Models, Molecular
Molecular Sequence Data
Mutation
NMD
Nonsense Mediated mRNA Decay - drug effects
Proteins
Receptors, Peptide - genetics
RNA, Messenger - genetics
RNA, Messenger - metabolism
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Summary:ABSTRACT 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. Hyaline Fibromatosis Syndrome is an autosomal recessive disease caused by mutations in ANTXR2. We show that targeting the non‐sense mediated mRNA decay pathway leads to a rescue of ANTXR2 protein in patients carrying 1 base insertion but not in those carrying 2 base insertions at the same site. This 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.
ISSN:1059-7794
1098-1004
DOI:10.1002/humu.22324