This section is intended for healthcare professionals outside of the US only. If you are a patient or a carer, please click here for further information.

Causes of Niemann-Pick type C disease

Niemann-Pick type C disease (NP-C) is an inherited, autosomal recessive condition linked to two genes; NPC1 (located on chromosome 18; q11-q12) and NPC2 (located on chromosome 14; q24.3). NP-C can be caused by a mutation on either gene.1 Approximately 95% of patients have a mutation on the NPC1 gene and 5% have a mutation on the NPC2 gene.1,2

To date, there are around 380 disease-causing . mutations in NPC1 recorded in various databases.Use of such tools is strongly encourged to aid diagnostic practice, but also improve our understading of the genetics of the disease.

Genotype-phenotype studies are limited but show good correlation between mutations and the severity of neurological disease. However, studies of large multiplex families show there to be no correlation with systemic manifestation of the disease.1

NPC1 and NPC2 proteins

The NPC1 and NPC2 gene products – NPC1 and NPC2 proteins – are important for normal cholesterol trafficking.

The NPC1 protein, a late-endosomal integral membrane protein, plays a major role in the trafficking of LDL-derived cholesterol between the late-endosomes, endoplasmic reticulum (ER), and plasma membrane.1–6

NPC1 has a large and compact membrane-spanning domain formed by 13 transmembrane helices, a middle luminal domain (MLD), a C-terminal luminal domain (CTD), and an N-terminal luminal domain (NTD).5,6

NPC1 contains a sterol-sensing domain (SSD; also present in other key proteins associated with cholesterol regulation), which is accessible vertically to the endosome lumen, and laterally to the lipid bilayer.5,6

The NPC2 protein is a small soluble lysosomal protein which aids lysosomal cholesterol solubilization and transport.1–3,5

NPC1 and NPC2 proteins act together to regulate cellular lipid trafficking and sterol homeostasis.2,3,5,6

Findings suggest a "hydrophobic hand-off model": following the binding of cholesterol, the NPC2 protein undergoes conformational change, enhancing its binding to the MLD of NPC1. Additional interactions between NPC1 and NPC2 are hypothesized to then create a cholesterol transfer tunnel. Cholesterol is then proposed to move through this tunnel, from NPC2 to the NTD of NPC1. The cholesterol molecule may then be transferred from the NTD of NPC1 to the transmembrane domain, before being deposited in the lysosomal lipid bilayer. Meanwhile, after transfer, the NPC2 protein’s conformation resets, promoting dissociation from NPC1 thereby allowing further cholesterol acquisition.5,6

NPC1 and NPC2 protein malfunction leads to impairment in the processing and utilization of endocytosed cholesterol. Subsequent accumulation of cholesterol, glycolipids and free sphingosine/sphinganine in extra-neural tissues and accumulation of GM2 and GM3 gangliosides in the brain might also be a result of these mutations. The accumulation of lipids eventually becomes toxic, damaging the cells and tissues and causing the neurologic symptoms of NP-C.1–3

References

  1. Vanier MT. Niemann-Pick disease type C. Orphanet J Rare Dis 2010;5:16.
  2. Vanier MT. Complex lipid trafficking in Niemann-Pick disease type C. J Inherit Metab Dis 2015;38:187–99.
  3. Vance JE.  Dysregulation of cholesterol balance in the brain: contribution to neurodegenerative diseases. Dis Model Mech. 2012;5:746–55.
  4. Vanier MT, Gissen P, Bauer P, et al. Diagnostic tests for Niemann-Pick disease Type C (NP-C): a critical review. Mol Genet Metab 2016;118:224–54.
  5. Li X, Wang J, Coutavas E, et al. Structure of human Niemann-Pick C1 protein. Proc Natl Acad Sci 2016;113:8212–7.
  6. Li X, Saha P, Li J, et al. Clues to the mechanism of cholesterol transfer from the structure of NPC1 middle luminal domain bound to NPC2. Proc Natl Acad Sci 2016;113:10079–84.