MURINE MODEL OF NIEMANN-PICK-C-DISEASE - MUTATION IN A CHOLESTEROL HOMEOSTASIS GENE

An integrated human-mouse positional candidate approach was used to id entify the gene responsible for the phenotypes observed in a mouse mod el of Niemann-Pick type C (NP-C) disease. The predicted murine NPC1 pr otein has sequence homology to the putative transmembrane domains of t he Hedgehog signaling molecule Patched, to the cholesterol-sensing reg ions of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and SREBP cleavage-activating protein (SCAP), and to the NPC1 orthologs id entified in human, the nematode Caenorhabditis elegans, and the yeast Saccharomyces cerevisiae. The mouse model may provide an important res ource for studying the role of NPC1 in cholesterol homeostasis and neu rodegeneration and for assessing the efficacy of new drugs for NP-C di sease.