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Every project supported by Gebert Rüf Stiftung is made accessible with a web presentation that informs about the core data of the project. With this public presentation, the foundation publishes the funding results achieved and contributes to the communication of science to society.


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


Für den Inhalt der Angaben zeichnet die Projektleitung verantwortlich.


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

Project data

  • Project no: GRS-044/09 
  • Amount of funding: CHF 450'000 
  • Approved: 28.10.2009 
  • Duration: 04.2010 - 09.2013 
  • Area of activity:  Rare Diseases, 2009 - 2014

Project management

Project description

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.

What is special about the project?

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.


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.


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).


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Persons involved in the project

Last update to this project presentation  12.05.2020