Types C and D Niemann-Pick disease are characterized by abnormal intracellular cholesterol homeostasis. The molecular lesion in these disorders causes: (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 are now widely used in medical practice for the diagnosis of Types C and D Niemann-Pick disease, identification of heterozygotes, and the prenatal diagnosis of these conditions. We have linked the NP-C mutation to chromosome 18 by positional cloning. We have obtained partial correction of the defective cholesterol metabolism with YACs within the NP-C defined interval on chromosome 18 q11. Identification of the gene will enable us to assess direct DNA diagnosis and initiate protein and gene replacement studies. The Golgi apparatus has been shown to regulate lysosomal cholesterol transport. Characterization of the cholesterol transporter as identified 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 lipidotic states such as atherosclerosis and potentially Alzheimer's disease.
