NIEMANN-PICK-C1-DISEASE GENE - HOMOLOGY TO MEDIATORS OF CHOLESTEROL HOMEOSTASIS

Niemann-Pick type C (NP-C) disease, a fatal neurovisceral disorder, is characterized by lysosomal accumulation of low density lipoprotein (L DL)-derived cholesterol. BY positional cloning methods, a gene (NPC1) with insertion, deletion, and missense mutations has been identified i n NP-C patients. Transfection of NP-C fibroblasts with wild-type NPC1 cDNA resulted in correction of their excessive lysosomal storage of LD L cholesterol, thereby defining the critical role of NPC1 in regulatio n of intracellular cholesterol trafficking. The 1278-amino acid NPC1 p rotein has sequence similarity to the morphogen receptor PATCHED and t he putative sterol-sensing regions of SREBP cleavage-activating protei n (SCAP) and 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductas e.