Niemann-Pick disease type C (NPC) differs from types A and B. While NPC-A and B result from sphingomyelinase deficiency, NPC-C is caused by a defect in cholesterol trafficking. Which protein is defective in NPC-C and what is its normal function?

• A Acid sphingomyelinase, which hydrolyzes sphingomyelin to ceramide and phosphocholine in lysosomes
• B NPC1 protein, a lysosomal membrane protein that transports unesterified cholesterol from lysosomes to the ER and plasma membrane ✓
• C Glucocerebrosidase (GBA1), which cleaves glucocerebroside to ceramide and glucose
• D Hexosaminidase A (HexA), which cleaves GM2 ganglioside in lysosomes

Explanation

NPC-C is caused by mutations in NPC1 (95% of cases) or NPC2 (5%). NPC1 is a lysosomal membrane protein that binds free cholesterol within the lysosome lumen (working together with NPC2, a soluble lysosomal cholesterol-binding protein) and exports it to the ER and plasma membrane. Defective NPC1 traps unesterified cholesterol in lysosomes, causing progressive neurodegeneration with vertical supranuclear gaze palsy, ataxia, and dementia in late infancy or adolescence. Filipin staining of fibroblasts demonstrating perinuclear cholesterol accumulation is a diagnostic test. This is mechanistically distinct from sphingomyelinase deficiency in types A/B.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.