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Niemann Pick type C disease

Niemann-Pick type C disease (NPC) is a lysosomal lipid storage disorder with autosomal recessive inheritance. The prevalence in Western Europe has been estimated to be approximately 1/150,000 living births Ikonen E and Holtta-Vuori M. At the cellular level, NPC is characterized by a defective transport of unesterified cholesterol and glycosphingolipids from lysosomes/late endosomes due to mutations in either NPC1 (95% of the cases) Tamura et al.H. or NPC2 (also called HE1) genes Naureckiene et al. Recently, another protein involved in this transport was identified in the plasma membrane and given its homology with NPC1 it was named NPC1L1 (Niemann-Pick C1-Like1) Davies et al.

The NPC1 gene maps to chromosome 18q11-12 and codes for NPC1 protein with 1278 amino-acids. It has 13 transmembrane domains, three large lumen hydrophilic loops, several small cytoplasmic loops and a C-terminal cytoplasmic tail. Transmembrane domains 3 to 7 share strong homology with sterol sensing domains, PTC, SCAP and NPC1L1. The lumen loops undergo glycosylation which may protect the protein from lysosomal and endosomal proteases. The C-terminal tail has a dileucine motif that may be involved in targeting NPC1 to the endoplasmic reticulum. However, the exact function of NPC1 remains uncertain and several scenarios have been suggested. It might be i) a primary transporter of fatty acids or phospholipids, and facilitate cholesterol movement, ii) a transporter of sphingolipids and gangliosides en masse, iii) it may have other functions Scott and Ioannou

The NPC2 gene maps to chromosome 14q24.3 and codes for the small glycoprotein NPC2 with 132 amino-acids long. Several isoforms have been observed reflecting heterogeneity of N-glycosylation sites. The phenotype and biochemical characteristics of fibroblasts deficient in NPC2 are similar to the ones deficient in NPC1, involving unesterified cholesterol, sphingomyelin, glucosylceramide and lactosylceramide, and ganglioside GM3. The precise function of NPC2 has not been elucidated yet. However, experimental data showed the protein does not function as a extracellular cholesterol sensor, instead it seems to bind cholesterol and transfer it between membranes and/or regulating cholesterol homeostasis Vanier and Millat

Given the phenotype similarities between NPC1 and NPC2 mutants it is easy to assume that these proteins may interact in function or in a pathway together facilitating cholesterol transport. Models have already been proposed regarding this matter, stating that NPC2 binds cholesterol subsequently interacting with NPC1 sterol-sensing domain and transport cholesterol from the lysosome.

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Niemann Pick type C disease