Contract grant sponsors: Swiss National Science Foundation; the Fondation Telethon Action Suisse; the Fondation S.A.N.T.E.-Vaduz/Aide au soutien des nouvelles therapies; the Gerbert Rüf Stiftung; Associazione I.S.I; the Fondation Minkoff.
In-Depth Analysis of Hyaline Fibromatosis Syndrome Frameshift Mutations at the Same Site Reveal the Necessity of Personalized Therapy
Article first published online: 19 APR 2013
© 2013 WILEY PERIODICALS, INC.
Volume 34, Issue 7, pages 1005–1017, July 2013
How to Cite
Yan, S. E., Lemmin, T., Salvi, S., Lausch, E., Superti-Furga, A., Rokicki, D., Dal Peraro, M. and van der Goot, F. G. (2013), In-Depth Analysis of Hyaline Fibromatosis Syndrome Frameshift Mutations at the Same Site Reveal the Necessity of Personalized Therapy. Hum. Mutat., 34: 1005–1017. doi: 10.1002/humu.22324
Communicated by Mark H. Paalman
- Issue published online: 18 JUN 2013
- Article first published online: 19 APR 2013
- Accepted manuscript online: 29 MAR 2013 01:25PM EST
- Manuscript Accepted: 20 MAR 2013
- Manuscript Received: 14 DEC 2012
- Swiss National Science Foundation
- Fondation Telethon Action Suisse
- Fondation S.A.N.T.E.-Vaduz/Aide au soutien des nouvelles therapies
- Gerbert Rüf Stiftung
- Associazione I.S.I
- Fondation Minkoff
- hyaline fibromatosis syndrome;
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.