Proteomics Profiling of Heterozygous and Homozygous Patients with ABCA1 Gene Mutation: A Tangier Disease Molecular Map

Tangier Disease (TD) is a rare inherited disorder with approximately 100 worldwide identified cases. Alpha-lipoprotein deficiency is the main characteristic of this disease, associated with a virtual absence of High Density Lipoproteins (HDL) in blood. Additional symptoms are mild hypertriglyceridemia, neuropathy and enlarged, orange-colored tonsils. Genetically TD is caused by mutations in the ABCA1 gene, which prevent the release of cholesterol and phospholipids from cells, leading to the accumulation of lipids within cells and body tissues. In this work a TD patient and his parental heterozygous were examined from a proteomics point of view. Plasma as well as proteome and secretome of circulating monocytes were analyzed. Plasma proteins underlined in TD the imbalance of lipid trafficking and metabolism, associated with the stimulation of pro-inflammatory pathways. Proteome and secretome of monocytes highlighted an extensive down regulation of mitochondrial enzymes and vesicular trafficking agents along with a substantial cytoskeletal rearrangement, suggesting a reduced activation state of monocytes from TD homozygous patient. This work is the first proteomics profiling of heterozygous and homozygous TD phenotypes and it suggests a TD case as a model to understand general mechanisms of lipid transport and metabolism and their linkage to inflammatory processes.