In 1997, researchers identified the location of the NPC1 gene on chromosome 18 (Table 2).3 Complementation studies, linkage analysis and mutation scanning studies have established that alterations or mutations in this gene cause the vast majority (90−95%) of cases of NPC.2,4–6 Notably, genetic linkage studies by Greer et al.5 established that the gene mutation responsible for so-called NPD was in fact an allelic variant of NPC1. In a second, much smaller, group of patients with NPC, mutations in NPC1 do not cause the disease. A second gene – NPC2 – is responsible for the NPC phenotype in these patients. HE1, mapped to chromosome 14, was recently identified as the gene underlying the NPC2 phenotype (Table 2).7,8
| Gene symbol | Chromosomal locus | Frequency/mutations | Protein name |
|---|---|---|---|
| NPC1 | 18q11–q12 | 90% of cases (sequence alterations) |
Niemann–Pick C1 protein |
| NPC2 | 14q24.3 | 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 (OMIM); protein name from Swiss-Prot protein knowledgebase.1
Although there is currently no direct evidence indicating other gene loci for NPC, some patients exhibiting the typical clinical and biochemical NPC phenotype have been shown not to possess mutations in either NPC1 or NPC2, and this has led researchers to suggest that other NPC gene loci may exist.
References:
1. Patterson MC. Niemann–Pick disease Type C. Gene Reviews 2007a (updated 9 July). Accessible at: www.geneclinics.org. Accessed 28th May 2009.
2. Carstea ED, Polymeropoulos MH, Parker CC et al. Linkage of Niemann–Pick disease type C to human chromosome 18. Proc Natl Acad Sci USA 1993;90:2002–4.
3. Carstea ED, Morris JA, Coleman KG et al. Niemann–Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science 1997;277:228–31.
4. Vanier MT, Duthel S, Rodriguez-Lafrasse C et al. Genetic 20. Greer WL, Dobson MJ, Girouard GS et al. Mutations in NPC1 highlight a conserved NPC1–specifi c cysteinerich domain. Am J Hum Genet 1999;65:1252–60.
5. Park WD, O’Brien JF, Lundquist PA et al. Identifi cation of 58 novel mutations in Niemann–Pick disease type C: correlation with biochemical phenotype and importance of PTC1–like domains in NPC1. Hum Mutat 2003;22:313–25.
6. Naureckiene S, Sleat DE, Lackland H et al. Identifi cation of HE1 as the second gene of Niemann–Pick C disease. Science 2000;290:2298–301.
7. Millat G, Chikh K, Naureckiene S et al. Niemann–Pick disease type C: spectrum of HE1 mutations and genotype/phenotype correlations in the NPC2 group. Am J Hum Genet 2001a;69:1013–21.
© 2007 Blackwell Publishing Limited. Reproduced by permission.