Niemann Pick Disease Type C2 (NPC2)

Mutations in the NPC2 gene associated with Niemann-Pick disease type C2 cause abnormally high cholesterol accumulation in cells. NPC2, a secreted soluble protein, binds cholesterol specifically with a much higher affinity than previously reported. Genetic and biochemical studies identified single amino acid changes that prevent both cholesterol binding and the restoration of normal cholesterol levels in mutant cells.

The amino acids that affect cholesterol binding surround a hydrophobic pocket in the NPC2 protein structure, identifying a candidate sterol-binding location. On the basis of evolutionary analysis and mutagenesis, 3 other regions of the NPC2 protein emerged as important, including 1 required for efficient secretion.