Towards preventing nodule formation in Hyaline Fibromatosis patients – Rare Diseases 2009

... lations économiques à l’EPFZ (2010–2014), codirecteur de Wyss Zurich depui... ... de la Fachhochschule Nordwestschweiz (2006–2010), vice-président de la Conféren... ... u FNS (2000–2009), doyen de la recherche de 2010 à 2014, puis vice-doyen ém&eacu...

Rare Diseases

... e umbrella organisation, ProRaris, was founded in 2010. And, last but not least, one sees a clear t...

Towards preventing nodule formation in Hyaline Fibromatosis patients – Rare Diseases 2009

Rédaction

Für den Inhalt der Angaben zeichnet die Projektleitung verantwortlich.

Coopération

This project is one of the five winners of the call 2009 «Rare Diseases - New Approaches». Project partner: EPFL

Données de projet

Numéro du projet: GRS-044/09
Subside accordé: CHF 450'000
Consentement: 28.10.2009
Durée: 04.2010 - 09.2013
Champs d'activité: Rare Diseases, 2009 - 2014

Direction du projet

Prof. Dr. Gisou van der Goot
Ecole Polytechnique Fédérale de Lausanne
EPFL SV GHI VDG, AI 3148 (Bâtiment AI)
Station 15
1015 Lausanne (Schweiz)
gisou.notexisting@nodomain.comvandergoot@epfl.notexisting@nodomain.comch

Description du projet

Hyaline fibromatosis syndrome is a rare autosomal recessive disease that is characterized by the accumulation of an amorphous hyaline material in the skin and other organs leading to large disabling subcutaneous tumors, gingival hypertrophy and flexion contractures of the joints. The most severe form of the disease leads to death before the age of two due to recurrent diarrhea and pulmonary infections. The gene responsible for the disease is Capillary Morphogenesis Gene 2 (CMG2), the physiological function of which has not been characterized but probably involves communication with the extracellular matrix. The best-characterized role of CMG2 is that of being the receptor for the anthrax toxin.

Development of large subcutaneous tumors is clearly one of the most debilitating aspects of the juvenile form of the disease. Formation of the tumors generally occurs at sites of mild repeated mechanical stress (nose, gums, back, anal region) or following mechanical injury (such as head bumping, or piano playing). The purpose of the project was to better understand the composition of the tumors, identify the cells that produce the hyaline material, determine the signaling pathways and mechanisms that impair the proper extracellular matrix metabolism with the aim of identifying inhibitors, that through local application (via creams, gels or patches) could prevent tumor formation following mechanical injury.

Quelles sont les particularités de ce projet?

Hyaline Fibromatosis Syndrome (HFS) is a monogenic disease. The responsible gene was identified very recently (in 2003). The first mention ever of this gene was only 2 years before (2001). Thus HFS is a new disease on a new gene that affects only very few individuals, but affects them very badly. Considering that research on the gene and the function of the encoded protein is in its infancy, hope for a cure in the medium future is very small. However, our understanding the formation of debilitating nodules has increased. Further studies will provide novel information on the role of a protein that is important for normal development in humans.

Etat/résultats intermédiaires

Through the study of patient mutations, our understanding of the effects of mutations has significantly increased. Our studies clearly show that the disease is due to a loss of function rather than the acquisition of a toxic function. We found that most missense mutations found in the first 12 exons of the protein lead to altered protein folding in the endoplasmic reticulum and thereby retention, preventing the protein from reaching its final destination. While these mutations appear to have the same ultimate consequence, i.e. the absence of a functional protein at the cell surface, our study illustrates that the potential therapeutic treatments must be designed specifically for each patient as a function of the specific mutations that the individual carries. Promisingly, we found using patient fibroblasts that borthezomib, a drug in clinical trials, leads to the rescue of a functional protein in certain patient fibroblasts.

During the third year of this grant, our efforts have been focused on understanding the consequence of the most frequent mutations in HFS, which correspond to insertions and deletions at a specific site. We found that all lead to premature mRNA degradation, which potentially points towards the NMD pathway as a therapeutic target. We however showed that indels at this site have different consequences. Double insertions lead to a frame shift, the consequence of which is the synthesis of a protein that has a misfolded cytosolic tail. This protein is rapidly degraded by the ER associated degradation pathway. Thus saving the cmg2 mRNA in patients harboring double insertions will not be beneficial. In contrast, single insertions lead to synthesis of a folded protein that is properly targeted to the cell surface and retains some of the CMG2 function. In the latter case, NMD targeting drugs could be beneficial.

These recent studies have been extremely important in highlighting the absolute requirement for in depth analysis of each mutation in order to design adapted drug therapies.

Since the start of the GRS granting period our knowledge about the consequences of HFS has tremendously increased. This might well have been the most rewarding period for a long time.

Publications

Deuquet, J., L. Abrami, A. Difeo, M.C. Ramirez, J.A. Martignetti, and F.G. van der Goot. Systemic hyalinosis mutations in the CMG2 ectodomain leading to loss of function through retention in the endoplasmic reticulum. Hum Mutat. 30:583-9 (2009);
Deuquet J, Lausch E, Guex N, Abrami L, Salvi S, et al. Hyaline Fibromatosis Syndrome inducing mutations in the ectodomain of anthrax toxin receptor 2 can be rescued by proteasome inhibitors. EMBO Mol Med 3: 208-221 (2011);
Deuquet, J., Lausch, E., Superti-Furga, A. & van der Goot, F. G. The dark sides of capillary morphogenesis gene 2. The EMBO journal 31, 3-13, doi:10.1038/emboj.2011.442 (2011);
Yan, S.E., T. Lemmin, S. Salvi, E. Lausch, A. Superti-Furga, D. Rokicki, M.D. Peraro, and F.G. van der Goot. In-Depth Analysis of Hyaline Fibromatosis Syndrome Frameshift Mutations at the Same Site Reveal the Necessity of Personalized Therapy. Human Mutation. 34:1005-1017 (2013).

Revue de presse

noch keine

Liens

http://vdg.epfl.ch (van der Goot laboratory)
http://www.associazioneisi.it/index.htm (Association for Hyaline Fibromatosis Syndrome)

Personnes participant au projet

Prof. Gisou van der Goot, Projektleiterin, gisou.vandergoot@epfl.ch

Dernière mise à jour de cette présentation du projet 12.05.2020

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Conseil de fondation

Rare Diseases

Towards preventing nodule formation in Hyaline Fibromatosis patients – Rare Diseases 2009

Rédaction

Coopération

Données de projet

Direction du projet

Description du projet

Quelles sont les particularités de ce projet?

Etat/résultats intermédiaires

Publications

Revue de presse

Liens

Personnes participant au projet