ArticleJournal of inherited metabolic disease2026
Differential Trafficking Phenotypes of NPC1 Mutant Proteins Reveal Distinct Cholesterol Accumulation Profiles.
Article in Journal of inherited metabolic disease, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
- Differential Trafficking Phenotypes of NPC1 Mutant Proteins Reveal Distinct Cholesterol Accumulation Profiles.Journal of inherited metabolic disease · 2026Article
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4 authors.
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Abstract
Niemann-Pick disease type C (NPC) is a rare autosomal recessive lysosomal storage disorder that affects approximately 1 in 100 000 live births. It is primarily caused by mutations in the NPC1 gene, which disrupts intracellular cholesterol transport and leads to lipid accumulation in late endosomes and lysosomes. This results in visceral dysfunction and progressive neurological deterioration. This study investigated the effects of three NPC1 disease-causing mutations (p.I1061T, p.D874V, and p.P1007A) on NPC1 biosynthesis, trafficking of NPC1, and cellular cholesterol levels. By expressing NPC1 mutants and wild-type NPC1 in NPC1 knockout Chinese hamster ovary cells (CHO-CT43), we analysed the trafficking patterns using Western blot based on endoglycosidase H sensitivity. We also examined lipid raft distribution and unesterified cholesterol accumulation using flotillin 2, filipin staining, and high-performance liquid chromatography (HPLC). Our findings revealed significant differences in NPC1 mutant expression levels and trafficking patterns, categorizing them into three distinct phenotypes: intracellularly retained, slow-trafficking, and finally wild-type-like mutants. Notably, the variations in NPC1 mutant expression and trafficking patterns in CHO-CT43 cells correlated with alterations in lipid rafts distribution and cellular cholesterol levels. The study demonstrated a clear association between cholesterol accumulation and NPC1 mutant trafficking phenotypes, with the p.I1061T variant exhibiting the most severe biochemical profile and highest cellular cholesterol levels. In conclusion, this study highlights a promising framework for elucidating the genotype-phenotype relationships in NPC and assessing their potential pathogenicity. These findings have significant implications for understanding the molecular mechanisms underlying NPC, and they propose personalized, targeted therapeutic strategies for this devastating disease.
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