CANDIDATE GENE ANALYSIS--INTEGRATIVE EFFORT TO CLONE NIEMANN-PICK TYPE C DISEASE

尼曼-皮克C型（NPC）是一种

Niemann-Pick type C (NPC) is an autosmal-recessive, neurovisceral disorder that is marked by neurological decline (progressive cognitive impairment, ataxia, dystonia, dysphagia, dysarthria, seizures, cataplexy and dementia) and hepatosplenomegaly resulting from cholesterol lipidosis. The gene (NPC-1) that is mutated in NPC was recently cloned and was found to be a membrane protein of unknown function but possibly involved in cholesterol homeostasis due to the presence of a sterol-sensing domain sequence in the protein. In order to study the function and role of the protein in cholesterol trafficking and homeostasis, we have succesfully generated 6 polyclonal antibodies against various segments of the protein. These antibodies are being used to identify subcellular localization of the NPC1 protein and to study its activity in the presence or absence of cholesterol. In addition, the NPC1 protein showed sequence homologies to worm (C. elegans) sequences. To exploit the worm system, null mutants were generated by EMU mutagenesis. The two homologous genes in worms have been successfully targeted and are now being characetrized for abnormal phenotype.