NPC2 – Niemann-Pick Disease Type C

NPC2 encodes a soluble lysosomal cholesterol-binding protein whose biallelic loss causes Niemann-Pick disease type C (NPC), an autosomal recessive neurovisceral lipid storage disorder characterized by hepatosplenomegaly, neurodegeneration, and psychiatric manifestations. Initial reports described two 17th-century French-Canadian descendants presenting adult-onset dementia with frontal lobe atrophy and vertical supranuclear gaze palsy, leading to discovery of a homozygous c.115G>A (p.Val39Met) mutation in NPC2 (PMID:12447927).

A comprehensive multi-family study of NPC2 variants in eight unrelated kindreds identified 16 mutant alleles across 16 patients, including two premature stop codons (p.Glu20Ter, p.Glu118Ter), a frameshift (c.27delG), a splice-site change (c.190+5G>A), and a missense (p.Ser67Pro), establishing clear genotype–phenotype correlations and segregation in recessive pedigrees (PMID:11567215). Most NPC2 mutations result in early pulmonary involvement and severe infantile disease, whereas a splice mutation yielding residual normal transcript is associated with juvenile onset and prolonged survival.

Clinically, NPC2 deficiency presents heterogeneously: neonatal respiratory distress with alveolar proteinosis, infantile hepatosplenomegaly and hypotonia, juvenile-onset ataxia with vertical gaze palsy, and adult-onset psychiatric symptoms including psychosis and dementia. Fibroblast filipin staining and cholesterol esterification assays remain diagnostic cornerstones, while oxysterol biomarkers (cholestane-3β,5α,6β-triol) facilitate rapid screening.

Functional studies demonstrate that missense NPC2 variants variably affect protein folding, glycosylation, and lysosomal targeting. Recombinant p.Val39Met traffics to lysosomes but exhibits mildly impaired cholesterol binding, whereas p.Cys47Phe, p.Ser67Pro, p.Cys93Phe, and p.Cys99Arg produce misfolded proteins that colocalize with endoplasmic reticulum and fail to clear lipid storage in NPC2–/– fibroblasts (PMID:15937921). Glycosylation of Asn⁵⁸ is critical for lysosomal delivery and function, underscoring the importance of NPC2’s N-glycan sites for cholesterol transport.

No conflicting evidence disputes NPC2’s definitive role in NPC. Current management includes symptomatic care and Miglustat to delay neurological progression, highlighting the importance of early genetic diagnosis and family counselling.

Key take-home: NPC2 mutations cause a definitive autosomal recessive NPC subtype; genetic testing of NPC2 should be included in diagnostic workflows for unexplained hepatosplenomegaly, ataxia, or psychiatric presentations alongside functional assays and oxysterol biomarkers.

References

• Annals of Neurology • 2002 • Frontal lobe atrophy due to a mutation in the cholesterol binding protein HE1/NPC2. PMID:12447927
• American Journal of Human Genetics • 2001 • Niemann-Pick disease type C: spectrum of HE1 mutations and genotype/phenotype correlations in the NPC2 group. PMID:11567215
• Human Mutation • 2005 • Niemann-Pick type C disease: subcellular location and functional characterization of NPC2 proteins with naturally occurring missense mutations. PMID:15937921

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