MOLECULAR PATHOLOGY OF MUTATIONS OF APOLIPOPROTEIN B AND MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN GENES IN FAMILIAL HYPOBETALIPOPROTEINEMIA

Familial Hypobetalipoproteinemia (FHBL) is a genetic disorder characterized by low levels of plasma cholesterol and some lipoproteins containing apolipoprotein B (apoB) as the main protein component. FHBL has a co-dominant transmission; each affected individuals has 50% chance of transmitting the disorder to the following generation. Subjects with FHBL are often referred to the clinic for the presence of a liver disease due to accumulation of fat (hepatic steatosis) sometimes associated with intestinal malabsorption of dietary fats. FHBL may be due to mutations in the apoB gene or in other genes not yet identified. Mutations in the apoB gene produce a variety of alterations of apoB which loses its capacity to form plasma lipoproteins in liver and intestine and to export lipids from these organs. These defects result in the accumulation of fat in the liver (hepatic steatosis) and in the intestine. Hepatic steatosis may predispose to more severe chronic liver disease such as steatohepatitis. In the present project we plan to investigate the biological effect of new mutations in the apoB gene we have discovered in recent past during the study of 53 FHBL patients with hepatic steatosis. We will also try to establish whether mutations in another gene (MTP gene), involved in the formation of lipoproteins in the liver and the intestine, can cause plasma lipids alterations and clinical manifestations similar to those observed in patients with FHBL due to apoB gene mutations. At the end of the study we will be able to better understand the molecular mechanisms underlying FHBL thus providing the bases for future treatments aimed at preventing fat accumulation in the liver and chronic liver damage.