Rare Loss-of-Function Variants in NPC1 Predispose to Human Obesity

Diabetes. 2017 Apr;66(4):935-947. doi: 10.2337/db16-0877. Epub 2017 Jan 27.


Some Shanghai Clinical Center f a role of Niemann-Pick type C1 (NPC1) for obesity traits. However, whether the loss-of-function mutations in NPC1 cause adiposity in humans remains unknown. We recruited 25 probands with rare autosomal-recessive Niemann-Pick type C (NP-C) disease and their parents in assessment of the effect of heterozygous NPC1 mutations on adiposity. We found that male NPC1+/- carriers had a significantly higher BMI than matched control subjects or the whole population-based control subjects. Consistently, male NPC1+/- mice had increased fat storage while eating a high-fat diet. We further conducted an in-depth assessment of rare variants in the NPC1 gene in young, severely obese subjects and lean control subjects and identified 17 rare nonsynonymous/frameshift variants in NPC1 (minor allele frequency <1%) that were significantly associated with an increased risk of obesity (3.40% vs. 0.73%, respectively, in obese patients and control subjects, P = 0.0008, odds ratio = 4.8, 95% CI 1.7-13.2), indicating that rare NPC1 variants were enriched in young, morbidly obese Chinese subjects. Importantly, participants carrying rare variants with severely damaged cholesterol-transporting ability had more fat accumulation than those with mild/no damage rare variants. In summary, rare loss-of-function NPC1 mutations were identified as being associated with human adiposity with a high penetrance, providing potential therapeutic interventions for obesity in addition to the role of NPC1 in the familial NP-C disease.

MeSH terms

  • Adult
  • Animals
  • Asian People / genetics*
  • Carrier Proteins / genetics*
  • Case-Control Studies
  • China
  • Diet, High-Fat*
  • Female
  • Frameshift Mutation
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Heterozygote
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Membrane Glycoproteins / genetics*
  • Mice
  • Middle Aged
  • Niemann-Pick C1 Protein
  • Obesity / genetics
  • Obesity, Morbid / genetics*
  • Phenotype
  • Proteins / genetics*
  • Young Adult


  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • NPC1 protein, human
  • Niemann-Pick C1 Protein
  • Npc1 protein, mouse
  • Proteins