MOLECULAR AND CELLLULAR ASPECTS OF AUTOSOMAL RECESSIVE HYPERCHOLESTEROLEMIA

Autosomal Recessive Hypercholesterolemia (ARH) is an inherited disorder of lipid metabolism causing severe elevation of plasma cholesterol and increased risk of premature coronary death. ARH individuals show a markedly reduced clearance rate of cholesterol- carrying plasma lipoproteins (LDL) and this is due to a liver-specific defect in the LDL receptor (LDL-R) pathway. Although several cases of ARH have been reported in other countries, it is noteworthy that most of ARH patients identified so far are of Sardinian origin. We recently discovered the gene responsible for ARH. Several ARH-causing mutations have been characterized including two that appear to be common in Sardinia. The identification of other ARH-causing mutations in Italian hypercholesterolemic patients as well as the definition of the frequency of the carrier status in the Sardinian population appear to be very important. ARH-gene encodes a protein which probably facilitates LDL-R function in liver cells. However, how the ARH protein functions is not clear This multi-center project is designed to: i) identify new ARH patients in Sardinia and continental Italy; ii) search for AHR-gene mutations in these patients and in other patients with genetically undefined hypercholesterolemias; iii) define the carrier frequency of the two common ARH-gene mutations in Sardinia; iv) find strategies for co-segregation analysis in ARH pedigrees; v) study the ARH-protein in fibroblasts of ARH patients and in a human hepatoma cell line regarded as a model of human hepatocytes vi) investigate the function of ARH protein and how it is regulated. This study will provide new insights on: a) the incidence of ARH and its clinical features; and b) the biology of ARH-protein as the basis for future therapeutic strategies.