The metabolic defect in patients with Types C and D Niemann-Pick disease has been shown to be due to abnormal intracellular cholesterol homeostasis. The molecular lesion in these disorders results in: (1) failure to down-regulate LDL receptors on cell membranes; (2) lack of down-regulation of HMGCoA reductase, a key enzyme in cholesterol biosynthesis; and (3) inability to up-regulate acyl cholesterol acyl CoA transferase, the enzyme that catalyzes the esterification of intracellular cholesterol. Tests have been developed and introduced into medical practice for the diagnosis of Types C and D Niemann-Pick disease and the identification of heterozygotes, and the prenatal diagnosis of these conditions. We have linked the NP-C mutation to chromosome No.18. Identification of the gene will enable us to assess direct DNA diagnosis and the initial protein and gene replacement studies. The Golgi apparatus has been shown to regulate lysosomal cholesterol transport. Characterization of the cholesterol transporter as idenfied by the NP-C mutation will provide the tools to begin to delineate the molecular mechanisms as well as cellular pathways of intracellular cholesterol transport. Armed with such information we will study cholesterol processing in normal cells and in pathogenic conditions represented, not only by the NP-C cell, but also by other cholesterol lipidodic states such as the atherogenic foam cell.
