• Home
  • Search Results
  • A nonsense loss-of-function mutation in PCSK1 contributes to dominantly inherited human obesity.

A nonsense loss-of-function mutation in PCSK1 contributes to dominantly inherited human obesity.

International journal of obesity (2005) (2014-06-04)
J Philippe, P Stijnen, D Meyre, F De Graeve, D Thuillier, J Delplanque, G Gyapay, O Sand, J W Creemers, P Froguel, A Bonnefond
ABSTRACT

A significant proportion of severe familial forms of obesity remain genetically elusive. Taking advantage of our unique cohort of multigenerational obese families, we aimed to assess the contribution of rare mutations in 29 common obesity-associated genes to familial obesity, and to evaluate in these families the putative presence of nine known monogenic forms of obesity. Through next-generation sequencing, we sequenced the coding regions of 34 genes involved in polygenic and/or monogenic forms of obesity in 201 participants (75 normal weight individuals, 54 overweight individuals and 72 individuals with obesity class I, II or III) from 13 French families. In vitro functional analyses were performed to investigate the mutation PCSK1-p.Arg80* which was identified in a family. A novel heterozygous nonsense variant in PCSK1 (p.Arg80*), encoding a propeptide truncated to less than two exons (out of 14), was found to co-segregate with obesity in a three-generation family. We demonstrated that this mutation inhibits PCSK1 enzyme activity and that this inhibition most likely does not involve a strong physical interaction. Furthermore, both mutations PCSK1-p.Asn180Ser and POMC-p.Phe144Leu, which had previously been reported to be associated with severe obesity, were also identified in this study, but did not co-segregate with obesity. Finally, we did not identify any rare mutations co-segregating with obesity in common obesity susceptibility genes, except for CADM2 and QPCTL, where we found two novel variants (p.Arg81His and p.Leu98Pro, respectively) in three obese individuals. We showed for the first time that a nonsense mutation in PCSK1 was likely to cause dominantly inherited human obesity, due to the inhibiting properties of the propeptide fragment encoded by the null allele. Furthermore, the present family sequencing design challenged the contribution of previously reported mutations to monogenic or at least severe obesity.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Calcium chloride solution, BioUltra, for molecular biology, ~1 M in H2O
Sigma-Aldrich
Calcium chloride, anhydrous, powder, 99.99% trace metals basis
Sigma-Aldrich
Calcium chloride, meets USP testing specifications
Sigma-Aldrich
Calcium chloride, anhydrous, BioReagent, suitable for insect cell culture, suitable for plant cell culture, ≥96.0%
Sigma-Aldrich
E-64, protease inhibitor
Sigma-Aldrich
Calcium chloride, AnhydroBeads, −10 mesh, ≥99.9% trace metals basis
Supelco
Calcium standard for AAS, analytical standard, 1.000 g/L Ca+2 in hydrochloric acid, traceable to BAM
Supelco
Calcium ion solution for ISE, 0.1 M Ca, analytical standard (for ion-selective electrodes)
Supelco
4-tert-Octylphenol monoethoxylate solution, 10 μg/mL in acetone, analytical standard
Supelco
4-tert-Octylphenol monoethoxylate solution, 1 μg/mL in acetone, analytical standard
Sigma-Aldrich
Calcium chloride, AnhydroBeads, −10 mesh, ≥99.99% trace metals basis