NPC1 – Niemann-Pick disease type C1

Niemann-Pick disease type C1 is an autosomal recessive neurovisceral lipid storage disorder caused by biallelic pathogenic variants in the NPC1 gene. Patients typically present in infancy or childhood with progressive neurological deficits, including ataxia, vertical supranuclear gaze palsy, hepatosplenomegaly, and variable pulmonary complications such as recurrent respiratory failure. Early molecular studies using SSCP in 13 unrelated families identified eight distinct missense mutations and multiple small deletions clustered in a conserved cysteine-rich luminal domain essential for cholesterol transport (PMID:10521290).

Inheritance is confirmed by compound heterozygous or homozygous NPC1 variants segregating with disease. In a cohort of 106 unrelated patients, genotype–phenotype analysis stratified individuals by missense variant topography and validated significant correlations between variant location and disease severity (PMID:38131230). A recurrent variant, c.3182T>C (p.Ile1061Thr), accounts for a large proportion of juvenile-onset cases and is deleterious when homozygous (PMID:33099109).

The allelic spectrum includes missense substitutions predominantly in the luminal cysteine-rich loop, loss-of-function frameshifts and nonsense mutations, splice-site changes, and rare large deletions. Functional assays demonstrate that NPC1 p.Ile1061Thr misfolds and is targeted for endoplasmic reticulum-associated degradation, reducing lysosomal cholesterol egress (t½=6.5 h versus 42 h; PMID:18216017). Heterozygous Npc1(+/–) mice exhibit partial motor dysfunction and increased anxiety by 9 weeks, indicating dosage sensitivity (haploinsufficiency) contributes to carriers’ vulnerability (PMID:26942423).

Mechanistic studies in cell and animal models reveal that NPC1 mediates late endosomal/lysosomal cholesterol export, working in concert with NPC2. Disruption of NPC1 triggers Beclin-1–dependent autophagy, linking lipid trafficking defects to cellular clearance pathways. Additionally, impaired antibacterial autophagy in NPC1-deficient macrophages predisposes to granulomatous intestinal inflammation akin to Crohn disease (PMID:26953272).

Collectively, over 100 unrelated probands with concordant biallelic NPC1 variants, autosomal recessive segregation, robust functional concordance in multiple model systems, and extensive genotype–phenotype correlations provide definitive evidence for NPC1 as the causal gene in Niemann-Pick disease type C1. Genetic testing of NPC1 and cholesterol trafficking assays are clinically actionable, guiding diagnosis, carrier screening, and therapeutic strategies.

References

• American journal of human genetics • 1999 • Mutations in NPC1 highlight a conserved NPC1-specific cysteine-rich domain. PMID:10521290
• Journal of inherited metabolic disease • 2024 • Development and validation of a new genotype-phenotype correlation for Niemann-Pick disease type C1. PMID:38131230
• Stem cell research • 2020 • Generation of an iPSC line (AKOSi006-A) from fibroblasts of an NPC1 patient, carrying the homozygous mutation p.Ile1061Thr (c.3182T>C) and a control iPSC line (AKOSi007-A) using a non-integrating Sendai virus system PMID:33099109
• The Journal of biological chemistry • 2008 • Niemann-Pick type C1 I1061T mutant encodes a functional protein that is selected for endoplasmic reticulum-associated degradation due to protein misfolding. PMID:18216017
• Neurotherapeutics • 2016 • Neurological Dysfunction in Early Maturity of a Model for Niemann-Pick C1 Carrier Status. PMID:26942423
• Gut • 2017 • Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease. PMID:26953272

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