ANALYSIS OF THE GIANT AXONAL NEUROPATHY FIBROBLASTS PROTEOME Van Coster R 1 , Mussche S 1 , De Paepe B 1 , Joel S 1 , Lissens W 2 , Rasic VM 3 , Murnane M 4 , Devreese B 5 1 Div Ped Neur, Univ Hosp, Ghent, Belgium 2 Center Med Gen, Univ Hosp, Brussels, Belgium 3 Clinic Child Neur and Psych, Univ, Belgrade, Serbia and Montenegro 4 Albany Med Coll, New York, United States 5 L-ProBe, Univ, Ghent, Belgium Background: Giant axonal neuropathy (GAN) is a hereditary disease characterized by severe loss of mental and motor functions. This disease is morphologically characterized by aggregation of intermediate filaments, a part of the cytoskeleton. Underlying mutations are found in the GAN gene encoding the protein gigaxonin which is involved in clearance of misfolded or damaged proteins by means of the ubiquitin-proteasome system, but the underlying mechanism still remains elusive. Methods: We compared the proteome of four control fibroblasts with that of four GAN patients by use of the quantitative iTRAQ 8-plex labeling method and mass spectrometry to test the hypothesis of accumulation of gigaxonin binding microtubule associated proteins (MAP's) in cultured skin fibroblasts and provide additional proteomics based insight into the cellular impact of gigaxonin mutations. Results: Among the differentially expressed proteins in GAN fibroblasts no upregulation of known gigaxonin binding MAP proteins could be demonstrated and no up or downregulation of cytoskeletal proteins in general was detected. Differentially expressed proteins were mainly associated with transcription/ translation and splicing and extracellular/membrane signaling pathways. Conclusions: Differentially expressed proteins indicated that the cytoskeleton organization was disturbed via several ways. Galectin-1 might have a central role is reorganization of the cytoskeleton. The Structural Genomics Consortium (SGC) spearheads the concept of open-source medical research by delivering structural biology knowledge on human proteins into the public domain. This wealth of 3D structures includes human enzymes implicated in inborn errors of metabolism. Understanding the effects of disease-associated mutations at the protein level is key to establish a causal relationship among sequence, 3D structure and patient phenotypes. To disseminate this structure-mutation data in an intuitive and approachable manner to the metabolic disease community, we are working with the Society for the Study of Inborn Errors of Metabolism (SSIEM) and Journal of Inherited Metabolic Disease (JIMD) to publish a collection of structure-mutation reports. Each article provides a jargon-free description of a protein structure and a table summary of associated missense mutations. Importantly the article is available online in an interactive visualisation format, where the reader can access each mutation to display a pre-programmed 3D scene, explore at will the molecular landscape in atomic detail and interpret the structural environment around the residue of interest. We hope that the interactive articles, the first of which is published in the 2011 June issue on fumarate hydratase deficiency, will close the knowledge gap between research communities and promote collaborations.