The NPC1 gene, mapped to chromosome 18 (18q11–q12) contains 25 coding regions (exons), varying in size from 74 to 788 bp and spread over 47 kb.4 More than 50 exonic polymorphisms have been described that do not give rise to any pathologic effect – they are simply non-adverse genetic variants.5 However, approximately 200 allelic variants have been identified for NPC1 that are suspected to have pathological effects.6,7
Most affected individuals with NPC1 mutations are compound heterozygotes (i.e., possess two different abnormal alleles, one on each of a chromosome pair) with single-base (point) mutations producing mis-sense mRNA transcripts that are unique to their family.5 Nonsense mutations, base-pair deletions and splice-site mutations have also been reported. One study in 143 unrelated patients with NPC demonstrated an overall mutation detection rate of 88%.1 Cases negative for NPC1 mutations showed a high proportion of inconclusive results in genetic complementation studies, which could be due to: a) a third genetic subgroup for NPC or, b) non-specificity of NPC biochemical testing.
NPC1 mutations commonly seen within distinct patient groups include G992W, a point mutation almost uniformly seen in Acadian patients from Nova Scotia who have previously been described as having NPD,8 and I1061T, a mutation that accounts for 15–20% of mutated alleles in Western Europe and the US.5 I1061T is followed in prevalence by the mutation, P1007A.5 In general, correlations between mutant NPC1 genotypes and NPC clinical phenotypes are difficult to pinpoint because of their compound heterozygous nature, although some distinct phenotypes have been suggested. In particular, I1061T appears to be associated with non-infantile forms of NPC,9 while A1054T, Q775P and C177Y mutant alleles were associated with early-onset disease with either biochemical or severe neurologic symptoms.7,10
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.11 NPC2 mutations are a little more varied than those in NPC1, with affected individuals expressing pathologic alleles in either homozygous or heterozygous fashion.2 One study conducted in eight families with NPC2 mutations found five mutations amongst sixteen mutant alleles, all except one of which were homozygous.3 A more recent study has reported a current total of 13 disease-causing mutations in NPC2.12
Genotype–phenotype correlations have also been identified for NPC2 mutations. Of the five mutations identified by Millat et al.,23 all but one were associated with a severe phenotype characterised by pulmonary infiltrates, respiratory failure, and death by age 4 years. Q45X, C47X and C99R mutations have also been associated with neonatal or infantile onset NPC, with death occurring in early childhood.12 However, adult-onset disease or31 survival into middle adult life has been described in association with V39M and S67P mutations in NPC2.12,13
References:
1. 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.
2. 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.
3. 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.
4. Morris JA, Zhang D, Coleman KG et al. The genomic organization and polymorphism analysis of the human Niemann–Pick C1 gene. Biochem Biophys Res Commun 1999;261:493–8.
5. Millat G, Baïlo N, Molinero S et al. Niemann–Pick C disease: use of denaturing high performance liquid chromatography for the detection of NPC1 and NPC2 genetic variations and impact on management of patients and families. Mol Genet Metab 2005;86:220–32.
6. Scott C, Ioannou YA. The NPC1 protein: structure implies function. Biochim Biophys Acta 2004;1685:8–13.
7. Fernandez-Valero EM, Ballart A, Iturriaga C et al. Identifi cation of 25 new mutations in 40 unrelated Spanish Niemann–Pick type C patients: genotype-phenotype correlations. Clin Genet 2005;68:245–54.
8. Greer WL, Riddell DC, Gillan TL et al. The Nova Scotia (type D) form of Niemann–Pick disease is caused by a G3097–->T transversion in NPC1. Am J Hum Genet 1998;63:52–4.
9. Millat G, Marçais C, Rafi MA et al. Niemann–Pick C1 disease: the I1061T substitution is a frequent mutant allele in patients of Western European descent and correlates with a classic juvenile phenotype. Am J Hum Genet 1999;65:1321–9.
10. Millat G, Marçais C, Tomasetto C et al. Niemann–Pick C1 disease: correlations between NPC1 mutations, levels of NPC1 protein, and phenotypes emphasize the functional signifi cance of the putative sterol-sensing domain and of the cysteine-rich luminal loop. Am J Hum Genet 2001b;68:1373–85.
11. Chikh K, Vey S, Simonot C et al. Niemann–Pick type C disease: importance of N-glycosylation sites for function and cellular location of the NPC2 protein. Mol Genet Metab 2004;83:220–30.
12. Chikh K, Rodriguez C, Vey S et al. Niemann–Pick type C disease: subcellular location and functional characterization of NPC2 proteins with naturally occurring missense mutations. Hum Mutat 2005;26:20–8.
13. Klünemann HH, Elleder M, Kaminski WE et al. Frontal lobe atrophy due to a mutation in the cholesterol binding protein HE1/NPC2. Ann Neurol 2002;52:743–9.
© 2007 Blackwell Publishing Limited. Reproduced by permission.