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Genetics and Epigenetics

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

International Journal of Obesity volume 39, pages 295–302 (2015)Cite this article

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Abstract

Background:

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.

Methods:

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.

Results:

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.

Conclusions:

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.

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Acknowledgements

We are sincerely indebted to all participants in the genetic study. We thank Marianne Deweirder and Frédéric Allegaert for their technical assistance and their management of DNA samples. We are grateful to Philippe Gallina for his invaluable help for the recruitment of families. This study was supported by: the Genoscope, the EU-founded EurOCHIP FP7 consortium, ‘Centre National de la Recherche Scientifique’ (CNRS), ‘FWO-Vlaanderen’ and ‘IWT’.

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Author notes

  1. J Philippe and P Stijnen: These authors contributed equally to this work.

Authors and Affiliations

  1. CNRS-UMR8199, Institut de Biologie de Lille, Lille Pasteur Institute, Lille, France

    J Philippe, D Meyre, F De Graeve, D Thuillier, J Delplanque, O Sand, P Froguel & A Bonnefond

  2. Lille 2 University, Lille, France

    J Philippe, D Meyre, F De Graeve, D Thuillier, J Delplanque, O Sand, P Froguel & A Bonnefond

  3. European Genomic Institute for Diabetes (EGID), Lille, France

    J Philippe, D Meyre, F De Graeve, D Thuillier, J Delplanque, O Sand, P Froguel & A Bonnefond

  4. Department of Human Genetics, Laboratory for Biochemical Neuroendocrinology, KU Leuven, Leuven, Belgium

    P Stijnen & J W Creemers

  5. Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada

    D Meyre

  6. Genoscope, Evry, France

    G Gyapay

  7. Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London, United Kingdom

    P Froguel

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Philippe, J., Stijnen, P., Meyre, D. et al. A nonsense loss-of-function mutation in PCSK1 contributes to dominantly inherited human obesity. Int J Obes 39, 295–302 (2015). https://doi.org/10.1038/ijo.2014.96

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