Niemann-Pick disease type C.

Niemann-Pick disease type C (NPC) is an autosomal recessive neurovisceral lipid storage with a wide spectrum of clinical phenotypes. At the cellular level, the disorder is characterized by accumulation of unesterified cholesterol and glycolipids in the lysosomal/late endosomal system. Approximatively 95% of patients have mutations in the NPC1 gene (mapped at 18q11) which encodes a large membrane glycoprotein primarily located to late endosomes. The remainder have mutations in the NPC2 gene (mapped at 14q24.3) which encodes a small soluble lysosomal protein with cholesterol-binding properties. The identical biochemical patterns observed in NPC1 and NPC2 mutants suggest that the two proteins function in a coordinate fashion. Identification of mutations revealed a complex picture of molecular heterogeneity, allowing genotype - phenotype correlations for both genes and providing insights into structure - function relationships for the NPC1 protein. Although a whole body of evidence suggests that the NPC1 and NPC2 proteins are involved in the cellular postlysosomal/late endosomal transport of cholesterol, glycolipids and other cargo, their precise functions and relationship remain unclear and are currently the subject of intense investigation. These studies, conducted in various models, should ultimately lead to a better understanding of the pathophysiology of NPC and new therapeutic approaches.