Abstracts
- 09/01/2012 - V. A. Huynh-Thu
- 09/01/2012 - R. Küffner
- 09/01/2012 - C. Ambroise
- 16/09/2011 - M. Bunster
- 27/04/2011 - P. Meyer
- 06/04/2011 - D. Débois
- 30/03/2011 - J. Wouters
- 28/01/2011 - J.-C. Lambert
- 13/12/2010 - J. Giard
- 17/11/2010 - B. Charloteaux
- 12/05/2010 - P. Soumillion
- 30/04/2010 - J.-P. Vert
- 14/04/2010 - X. Tordoir
- 24/03/2010 - J.C. Voegel
- 17/03/2010 - A. Turtoi
- 24/02/2010 - L. Palmeira
- 27/01/2010 - D. Devos
- 09/12/2009 - F. Heuze
- 25/11/2009 - L. Geris
- 19/11/2009 - V. Gabelica
- 14/10/2009 - G. Zocchi
- 30/09/2009 - K. Van Steen
- 12/06/2009 - D. Gianola
- 05/06/2009 - F. J. Theis
- 02/06/2009 - M. Babu
- 07/05/2009 - J. Eyzaguirre
- 22/04/2009 - E. Bullinger
- 08/04/2009 - F. Francis
- 04/03/2009 - Kick-off
Structural features and interaction defects of point mutations in proteins associated with Human Mendelian disorders
Fabien Heuze
Date and place: Wednesday December, 9th 12:30 at I.Raik (B31)
Appropriate function of living cells is carried out through an integrated network of interacting macromolecules (DNA, RNA or proteins) and metabolites connected by biochemical or physical interactions, represented in interactome models by “nodes” and links or “edges”, respectively. Alterations of this intricate cellular machinery trigger human genetic diseases. Adequate modeling to decrypt the underlying mechanisms of these disorders is obviously a necessity.
The goal of this work was to explore an alternative model to the “loss of gene product” model traditionally proposed in the literature. In brief, human genetic diseases are thought to result in general from major alterations of genes that lead to the absence of any functional product encoded by those genes. Here, we distinguished two types of interactome perturbations that correspond either to a gross alteration of the gene product in the “loss of gene product” or “node removal” model, or to perturbations of specific interactions in the “edge-specific” or “edgetic” perturbation model. In a test of this model, we built an extensive, non-redundant and representative dataset of 3,664 missense mutations associated with human Mendelian disorders that could be mapped on high quality protein 3D structures. Our hypothesis was that buried mutations preferentially lead to “node removal”, whereas mutations at the surface of the protein preferentially lead to “edgetic perturbations”, causing different diseases.
By structural analyses we found that (i) mutated residues mapped on the protein 3D structures are on average more buried than all the residues of these structures, (ii) about one third of the mutations are largely buried while another third are largely exposed, the last third occupying an intermediate position, (iii) mutated residues associated with autosomal dominant diseases are on average more accessible than the ones associated with autosomal recessive disorders. These results demonstrate our model, since both types of network perturbations, “node removal” and “edgetic perturbations”, are well represented and induce distinct types of diseases, as autosomal recessive and autosomal dominant diseases are enriched in “node removal” and “edgetic perturbations”, respectively. As further emphasized by the study of complement factor H disease-associated mutations, distinguishing “node removal” from “edgetic perturbations” would help in the understanding and in the treatment of human genetic diseases.