Abstract
While homozygous pathogenic mutations in the NPC1 gene cause Niemann-Pick type C1 disease, heterozygous mutations cause highly-penetrant obesity. We aimed to investigate the prevalence of NPC1 mutations and their signatures of natural selection in 122,678 exome sequenced participants from six ethnic groups in the Genome Aggregation Database. Pathogenic missense coding mutations were identified by in silico tools and the ClinVar database. Signatures of natural selection were assessed by the probability of NPC1 being loss-of-function mutation intolerant and Z-scores of observed/expected synonymous and non-synonymous mutation ratios. There was no evidence of negative selection observed for synonymous, non-synonymous and loss-of-function mutations. However, there were significant ethnic differences in the prevalence of heterozygous pathogenic NPC1 mutations ranging from 0.56% in Ashkenazi Jewish to 3.26% in African/African Americans (5.8-fold difference). Four homozygous carriers of pathogenic NPC1 mutations were also identified, belonging to the South Asian population. In conclusion, NPC1 mutations are consistent with a model of balanced selection, where heterozygotes and homozygotes have higher and lower reproductive fitness, respectively. Therefore, NPC1 heterozygous mutations may account for a substantial and ethnic-dependent percentage of obesity in the general population, while NPC1 homozygous mutations may be frequent in the South Asian populations and warrants more investigation.
Highlights
While homozygous pathogenic mutations in the Niemann–Pick C1 (NPC1) gene cause Niemann-Pick type C1 disease, heterozygous mutations cause highly-penetrant obesity
Similar sex-specific associations were found in NPC1 heterozygous knock-out (NPC1+/−) mice fed a high fat diet (HFD) with significant differences in body weight observed as the mice reached m aturity[14]
Description of the NPC1 pathogenic mutations identified in Genome Aggregation Database (gnomAD)
Summary
While homozygous pathogenic mutations in the NPC1 gene cause Niemann-Pick type C1 disease, heterozygous mutations cause highly-penetrant obesity. Young patients of the same population carrying heterozygous NPC1 LOF mutations had a fivefold increase in the risk of obesity, only the associations in men reached significance when the results were stratified by sex[14]. Studies have reported that N PC1+/− mice fed a high-fat diet are physiologically characterized with increased liver glycolysis and lipogenesis, and decreased adipose lipolysis through impaired feedback inhibition of the sterol regulatory element binding protein-1 (SREBP-1) pathway These metabolic disturbances lead to lipid accumulation in the liver and adipose tissue with resultant weight gain in NPC1+/− mice compared to NPC1+/+ mice fed an identical diet, thereby confirming the gene-diet interaction[23]. Individuals with homozygous mutations for sickle hemoglobin develop sickle cell anemia, a fatal disease if left u ntreated[29], while heterozygotes have a protective advantage against the Plasmodium falciparum malaria infection[30]
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