Niemann-Pick type C disease: NPC1 mutations associated with severe and mild cellular cholesterol trafficking alterations

Abstract

Niemann-Pick type C disease (NPC) is a rare neurodegenerative disorder characterised by lysosomal/late endosomal accumulation of endocytosed unesterified cholesterol and delayed induction of cholesterol homeostatic reactions. The large majority of mutations in the NPC1 gene described thus far have been associated with severe cellular cholesterol trafficking impairment (classic biochemical phenotype, present in about 85% of NPC patients). In our population of 13 unrelated NP-C1 patients, among which 12 were of Portuguese extraction, we observed an unusually large proportion of families presenting mild alterations of intracellular cholesterol transport (variant biochemical phenotype), without strict correlation between the biochemical phenotype and the clinical expression of the disease. Mutational studies were carried out to compare molecular lesions associated with severe and mild cholesterol traffic impairment. Levels of NPC1 protein were studied by Western blot in cultured fibroblasts of four patients with homozygous mutant alleles. Ten novel mutations were identified (Q92R, C177Y, R518W, W942C, R978C, A1035V, 2129delA, 3662delT, IVS23+1 G>A and IVS16-82 G>A). The mutational profile appeared to be correlated with the biochemical phenotype. Splicing mutations, I1061T and A1035V, corresponded to "classic" alleles, while three missense mutations, C177Y, R978C and P1007A, could be defined as "variant" alleles. All "variant" mutations described so far appear to be clustered within the cysteine-rich luminal loop between TM 8 and 9, with the remarkable exception of C177Y. The latter mutant allele, at variance with P1007A, was correlated to a decreased level of NPC1 protein and a severe course of the disease, and disclosed a new location for "variant" mutations, the luminal loop located at the N-terminal end of the protein.

The Spectrum of Niemann-Pick Type C Disease in Greece

“…In our cohort of patients the mutation was also identified either in homozygosity or heterozygosity in three patients all with the variant filipin staining pattern. In homozygosity it was associated with the adult form of the disease in siblings #12 and #13, in good accordance with other studies (Ribeiro et al 2001;Stampfer et al 2013) whereas in heterozygosity with the missense mutation p.S940L(c.2819C>T) (Greer et al 1999) it was associated with juvenile onset of disease (Patient #11). Patient #14 was shown to be homozygous for the mutation IVS2+5G>A (c.190+5G>A) in the NPC2 gene.…”

“…In the NPC1 patients, 12 different mutations and nine different genotypes were identified. Eight of the mutations had been previously described: p.E1089K (3265G>A) (Sun et al 2001), p.F284Lfs*26 (c.852delT) (Fancello et al 2009), p. A1132P(c.3394G>C) (Mavridou et al 2014), del promoter region and exons 1-10 (Rodriguez-Pascau et al 2012), p. R1186H(c.3557G>A) (Carstea et al 1997), p.P1007A (c.3019C>G) (Greer et al 1999), p.Q92R(c.275A>G) (Ribeiro et al 2001), and p.S940L(c.2819C>T) (Greer et al 1999). The mutations p.A1132P(c.3394G>C) and the large deletion of the promoter region and of exons 1-10 have only been described in Greek patients (included in this report as #2, #3, #7).…”

Prevalence of lysosomal storage diseases in Portugal

“…In fact, a wide genetic heterogeneity was observed, the I1061 T allele of the NPC1 gene, which represents 15% of the mutant alleles in British and French NPC patients, 19 represents only 6% of the NPC1-mutated alleles in the Portuguese NPC patients. 20 In conclusion, as a group, LSDs can be considered as a very frequent inborn error of metabolism in the Portuguese Population, presenting a birth prevalence (1/4000 live births) higher than birth prevalence reported in the case of PKU (1/12 000 live births) and congenital hypothyroidism (1/6000 live births). 21 …”

Treatment of Human Fibroblasts Carrying NPC1 Missense Mutations with MG132 Leads to an Improvement of Intracellular Cholesterol Trafficking

“…Only three relative frequent mutations have been found within distinct patient groups: the p.G992W, almost exclusively seen in Acadian patients from Nova Scotia (Greer et al 1998), the p.P1007A found in about 15% of mutated alleles in different European populations (Ribeiro et al 2001;Fancello et al 2009) and the p.I1061T that accounts for 15-20% of mutated alleles in Western Europe and USA (Millat et al 1999;Sun et al 2001;Park et al 2003;Millat et al 2005). However, a study performed in 44 Italian NPC patients showed that the p.I1061T mutation is much less common in Italy, representing only a 4.7% of the NPC1 alleles (Fancello et al 2009).…”