Niemann-Pick Type C (NP-C) is an autosomal-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. Our collaborators from NINDS have localized NP-C to 18q11-q12, more specifically in a 2 cM interval between markers D18S44 and D18S480. We used an integrative approach that involved the utilization of genomic and cDNA clones for complementation studies of NP-C cells, as well as the use of mouse backcross analysis of naturally occurring murine models to supplement the recombinant studies in reducing rapidly the candidate interval. Succesful contig assembly of the region in yeast artificial chromosome (YACs), (bacterial artificial chromosome) BACs and cosmids; sequence analyses; and mutation searches in candidate genes recently resulted in the identification of a 4.9 kb transcript that encodes a membrane protein of 142 kD that is mutated in NP-C patients. The role of this gene, NPC-1, in cholesterol trafficking and homeostasis will be examined using immunohistochemistry, cellular biology and modeling in other organisms.
