The long term goal of this project is to identify the gene responsible for Niemann-Pick Type C (NP-C) and to study its role in the pathogenesis of the disorder. NP-C is an autosomal- recessive, neurovisceral lipid storage disorder and presents as variable hepatosplenomegaly, vertical supranuclear ophthalmoplegia, progressive ataxia, dystonia, and dementia. Using human positional cloning and crosses with spontaneous mouse modles, we have identified the gene responsible for this disorder. First, we used a 0.1cM mouse genetic linkage map in the region containing m-npc using a series of intersubspecific mouse backcrosses. We next integrated the murine genetic mapwith the human genetic and physical maps using cloned DNA fragments generated from the contig of human DNA containing the NP-C gene. Finally we evaluated genes as candidates for NP-C from a pool of cDNA clones and trapped exon fragments isolated from the human physical contig. Using Northern blot, Southern blot, SSCP and sequencing analyses using samples isolated from spontaneous mouse mutants in comparison to their isogenic wild type controls we found that one gene, NPC1 has a retrotransposon insertion resulting in a loss-of-function of the normal gene product in mutatn mice. We have also found mutations in human individuals with NPC.
