The Spectrum of Niemann-Pick Type C Disease in Greece

Mavridou, Irene; Dimitriou, Evangelia; Vanier, Marie T.; Vilageliu, Lluı̈sa; Grinberg, Daniel; Latour, Philippe; Xaidara, Athina; Lycopoulou, Lilia; Bostantjopoulou, Sevasti; Zafeiriou, Dimitrios I.; Michelakakis, Helen

doi:10.1007/8904_2016_41

Cited by 14 publications

(19 citation statements)

References 32 publications

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“…The most frequent NPC1 mutation in our cohort was the p.F284Lfs*26 variant found in 5.8% of the alleles. This variant has been reported in the Greek population with a frequency of 3.8% [10]. The second most frequent mutation in our cohort was the p.P1007A, found in 5.2% of alleles.…”

Section: Npc1 and Npc2 Mutational Profilesupporting

confidence: 62%

“…As previously reported, the recurrent p.I1061T variant, which presents an allele frequency of 23% and 18% in patients from the United Kingdom [8] and France [7], respectively, accounted for only 3.9% of Italian alleles. A lower frequency was also reported in Spain [9], Greece [10], and the Czech Republic [30]. The most frequent NPC1 mutation in our cohort was the p.F284Lfs*26 variant found in 5.8% of the alleles.…”

Section: Npc1 and Npc2 Mutational Profilesupporting

confidence: 40%

“…To date, 486 mutations in the NPC1 gene have been reported worldwide (HGMD Professional database, Qiagen), and most of them are private or reported in a small number of families, with few exceptions. Indeed, the p.I1061T variant accounts for 20-25% of alleles in patients diagnosed in France [7] or the United Kingdom [8], but it seems to be much less frequent in countries from southern Europe [9,10]. The second most frequent mutation of NPC1 in Europe is the p.P1007A, strongly associated with the variant biochemical phenotype [11,12].…”

Section: Introductionmentioning

confidence: 99%

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Molecular Genetics of Niemann–Pick Type C Disease in Italy: An Update on 105 Patients and Description of 18 NPC1 Novel Variants

Dardis

Zampieri

Gellera

et al. 2020

JCM

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Niemann-Pick type C (NPC) disease is an autosomal recessive lysosomal storage disorder caused by mutations in NPC1 or NPC2 genes. In 2009, the molecular characterization of 44 NPC Italian patients has been published. Here, we present an update of the genetic findings in 105 Italian NPC patients belonging to 83 unrelated families (77 NPC1 and 6 NPC2). NPC1 and NPC2 genes were studied following an algorithm recently published. Eighty-four different NPC1 and five NPC2 alleles were identified. Only two NPC1 alleles remained non detected. Sixty-two percent of NPC1 alleles were due to missense variants. The most frequent NPC1 mutation was the p.F284Lfs*26 (5.8% of the alleles). All NPC2 mutations were found in the homozygous state, and all but one was severe. Among newly diagnosed patients, 18 novel NPC1 mutations were identified. The pathogenic nature of 7/9 missense alleles and 3/4 intronic variants was confirmed by filipin staining and NPC1 protein analysis or mRNA expression in patient’s fibroblasts. Taken together, our previous published data and new results provide an overall picture of the molecular characteristics of NPC patients diagnosed so far in Italy.

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Section: Npc1 and Npc2 Mutational Profilesupporting

confidence: 62%

Section: Npc1 and Npc2 Mutational Profilesupporting

confidence: 40%

Section: Introductionmentioning

confidence: 99%

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Molecular Genetics of Niemann–Pick Type C Disease in Italy: An Update on 105 Patients and Description of 18 NPC1 Novel Variants

Dardis

Zampieri

Gellera

et al. 2020

JCM

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“…The p.R1186H in homozygous state leads to a severe reduction of NPC1 protein (this study and [32]). It has constantly been associated with a severe (early infantile or late infantile) neurological phenotype, [32,51] as well as pronounced abnormalities of cellular cholesterol processing [32,51]. In compound heterozygosity, the observed protein level appears to depend on the second allele.…”

Section: Discussionmentioning

confidence: 99%

Transcript, protein, metabolite and cellular studies in skin fibroblasts demonstrate variable pathogenic impacts of NPC1 mutations

Musalkova

Majer

Kuchař

et al. 2020

Orphanet J Rare Dis

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Background: Niemann-Pick type C (NP-C) is a rare neurovisceral genetic disorder caused by mutations in the NPC1 or the NPC2 gene. NPC1 is a multipass-transmembrane protein essential for egress of cholesterol from late endosomes/lysosomes. To evaluate impacts of NPC1 mutations, we examined fibroblast cultures from 26 NP-C1 patients with clinical phenotypes ranging from infantile to adult neurologic onset forms. The cells were tested with multiple assays including NPC1 mRNA expression levels and allele expression ratios, assessment of NPC1 promoter haplotypes, NPC1 protein levels, cellular cholesterol staining, localization of the mutant NPC1 proteins to lysosomes, and cholesterol/cholesteryl ester ratios. These results were correlated with phenotypes of the individual patients. Results: Overall we identified 5 variant promoter haplotypes. Three of them showed reporter activity decreased down to 70% of the control sequence. None of the haplotypes were consistently associated with more severe clinical presentation of NP-C. Levels of transcripts carrying null NPC1 alleles were profoundly lower than levels of the missense variants. Low levels of the mutant NPC1 protein were identified in most samples. The protein localised to lysosomes in cultures expressing medium to normal NPC1 levels. Fibroblasts from patients with severe infantile phenotypes had higher cholesterol levels and higher cholesterol/cholesteryl ester ratios. On the contrary, cell lines from patients with juvenile and adolescent/adult phenotypes showed values comparable to controls. Conclusion: No single assay fully correlated with the disease severity. However, low residual levels of NPC1 protein and high cholesterol/cholesteryl ester ratios associated with severe disease. The results suggest not only low NPC1 expression due to nonsense mediated decay or low mutant protein stability, but also dysfunction of the stable mutant NPC1 as contributors to the intracellular lipid transport defect.

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“…[49] The p.R1186H in homozygous state leads to a severe reduction of NPC1 protein (this study and [32]) It has constantly been associated with a severe (early infantile or late infantile) neurological phenotype, [32,50] as well as pronounced abnormalities of cellular cholesterol processing. [32,50] but also direct filipin staining and UC/CE ratios were at the control level implying that the cholesterol transport function is less compromised. The latter findings are in good agreement with the well-known observation of a correlation between p.P1007A and a near normal cholesterol trafficking (so-called "variant") profile, usually even in a compound heterozygous status.…”

Section: Discussionmentioning

confidence: 80%

Transcript, protein, metabolite and cellular studies in skin fibroblasts demonstrate variable pathogenic impacts of NPC1 mutations.

Musalkova

Majer

Kuchař

et al. 2020

Preprint

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Background: Niemann-Pick type C (NP-C) is a rare neurovisceral genetic disorder caused by mutations in the NPC1 or the NPC2 gene. NPC1 is a multipass-transmembrane protein essential for egress of cholesterol from late endosomes/lysosomes. To evaluate impacts of NPC1 mutations, we examined fibroblast cultures from 26 NP-C1 patients with clinical phenotypes ranging from infantile to adult neurologic onset forms. The cells were tested with multiple assays including NPC1 mRNA expression levels and allele expression ratios, assessment of NPC1 promoter haplotypes, NPC1 protein levels, cellular cholesterol staining, localization of the mutant NPC1 proteins to lysosomes, and cholesterol/cholesteryl ester ratios. These results were correlated with phenotypes of the individual patients. Results: Overall we identified 5 variant promoter haplotypes. Three of them showed reporter activity decreased down to 70% of the control sequence. None of the haplotypes were consistently associated with more severe clinical presentation of NP-C. Levels of transcripts carrying null NPC1 alleles were profoundly lower than levels of the missense variants. Low levels of the mutant NPC1 protein were identified in most samples. The protein localised to lysosomes in cultures expressing medium to normal NPC1 levels. Fibroblasts from patients with severe infantile phenotypes had higher cholesterol levels and higher cholesterol/cholesteryl ester ratios. On the contrary, cell lines from patients with juvenile and adolescent/adult phenotypes showed values comparable to controls. Conclusion: No single assay fully correlated with the disease severity. However, low residual levels of NPC1 protein and high cholesterol/cholesteryl ester ratios associated with severe disease. The results suggest not only low NPC1 expression due to non-sense mediated decay or low mutant protein stability, but also dysfunction of the stable mutant NPC1 as contributors to the intracellular lipid transport defect.

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The Spectrum of Niemann-Pick Type C Disease in Greece

Cited by 14 publications

References 32 publications

Molecular Genetics of Niemann–Pick Type C Disease in Italy: An Update on 105 Patients and Description of 18 NPC1 Novel Variants

Molecular Genetics of Niemann–Pick Type C Disease in Italy: An Update on 105 Patients and Description of 18 NPC1 Novel Variants

Transcript, protein, metabolite and cellular studies in skin fibroblasts demonstrate variable pathogenic impacts of NPC1 mutations

Transcript, protein, metabolite and cellular studies in skin fibroblasts demonstrate variable pathogenic impacts of NPC1 mutations.

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