<unk> –Pick<unk>  C is biochemically, genetically and clinically distinct from<unk> –Pick<unk> s A or and B. In<unk> s A and B, there is complete or partial deficiency of the lysosomal enzyme called acid sphingomyelinase. In<unk> –Pick<unk>  C, the protein product of the major mutated gene NPC1 is not an enzyme but appears to function as a transporter in the endosomal-lysosomal system, which moves large water-insoluble molecules through the cell. The protein coded by the NPC2 gene more closely resembles an enzyme structurally but seems to act in cooperation with the NPC1 protein in transporting molecules in the cell. The disruption of this transport system results in the accumulation of cholesterol and glycolipids in lysosomes. Cholesterol and glycolipids have varied roles in the cell. Cholesterol is a major component of cell plasma membranes, which define the cell as a whole and its organelles. It is also the basic building block of steroid hormones, including neurosteroids. In<unk> –Pick<unk>  C, large amounts of free or unesterified cholesterol accumulate in lysosomes, and leads to relative deficiency of this molecule in multiple membranes and for steroid synthesis. The accumulation of glycosphingolipids in the nervous system has been linked to structural changes, namely ectopic dendritogenesis and meganeurite formation, and has been targeted therapeutically. Several theories have attempted to link the accumulation of cholesterol and glycolipids in the lysosomes with the malfunction of the NPC-1 protein. * Neufeld et al. hypothesized that the accumulation of mannose 6-phosphate receptors (MPRs) in the late endosome signals failure of retrograde trafficking of cholesterol via the trans Golgi network. * Another theory suggests that the blockage of retrograde cholesterol breakdown in the late endosome is due to decreased membrane elasticity and thus the return vesicles of cholesterol to the trans Golgi Network cannot bud and form. * Iouannou, et al. have described similarities between the NPC1 protein and members of the resistance-nodulation-division (RND) family of prokaryotic permeases, suggesting a pumping function for NPC1. * Recent 2008 evidence indicates that NPC-1 may play an important role in calcium regulation.
Niemann–Pick disease, type C
Niemann–Pick disease, SMPD1-associated
Wilson–Mikity syndrome
Haemochromatosis type 3
Hemochromatosis type 4
Wilson's disease
Mowat–Wilson syndrome
Bannayan–Riley–Ruvalcaba syndrome