NPC1 and NPC2 Gene Mutations
In 1997, researchers at the National Institute of Health identified the location of the NPC1 gene on chromosome 18 (See Table below). More than 250 mutations of the NPC1 gene located on chromosome 18 have been identified and are responsible for 95% of reported cases. The NPC1 gene contains 25 coding regions (exons), varying in size from 74 to 788 bp and spread over 47 kb (Morris et al, 1999).
The NPC2 gene, which has been mapped to chromosome 14 (14q24.3), has five exons and produces a single mRNA transcript of 0.9 kb in all tissues where it is expressed (Chikh et al, 2004). NPC2 mutations are a little more varied than those in NPC1, with affected individuals expressing pathologic alleles in either homozygous (similar) or heterozygous (varied) fashion (Naureckiene et al, 2000).
90% of cases (sequence alterations)
4% of cases (sequence alterations)
Epididymal secretory protein E1
Sources: Gene symbol from HUGO gene nomenclature committee; chromosomal locus, locus name, critical region and complementation group from Online Mendelian Inheritance in Man database (ONIM); protein name from Swiss-Prot protein knowledgebase (Patterson, 2007). NPC2 is more varied than those in NPC1, with affected individuals expressing pathologic alleles in either homozygous (similar) or heterozygous (varied) fashion (Naureckiene et al, 2000).
Mutations in either of these two genes, NPC1 or NPC2, may cause the disease. The NPC1 gene encodes a large membrane glycoprotein with mostly a late endosomal localization. The NPC2 gene encodes a small soluable lysosomal protein that bind cholesterol with high affinity. However, they both result in a similar cellular lesion, including a unique impairment in processing and utilization of endocytosed cholesterol that could explain cholesterol storage and secondary alterations of sphingomyelin metabolism in extra neural tissues. The current theory is that both work in tandem or sequentially. However, the exact functions of both these proteins are still unclear.
As a result, patients with NPC1 and NPC2 mutations are not distinguishable clinically and symptomatic disease management is identical. There may be other gene mutations, yet to be identified, that could also be involved in this disease.
Within the cells, these mutations create abnormalities in the transportation of cholesterol, gylcosphingolipids and sphingosine between cells which leads the accumulation of these lipids in the late-endosomal/lysosomal intracellular compartment and excess bulk build up in various tissues. Storage like unesterified cholesterol, sphingomyelin, bis(monoacylglycero)phosphate, glycosphingolipids and sphingosine in the liver and spleen and glucosylceramide, lactosylceramide and particularly GM2 and GM3 gangliosides in the brain (source: Vanier Orphanet Journal of Rare Diseases 2010).