ArticleInternational journal of obesity (2005)2015
A nonsense loss-of-function mutation in PCSK1 contributes to dominantly inherited human obesity.
Article in International journal of obesity (2005), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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26 citing papers in PubMed, 73 citations in OpenAlex.
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- High-Throughput Screening of Mouse Gene Knockouts Identifies Established and Novel High Body Fat Phenotypes.Diabetes, metabolic syndrome and obesity : targets and therapy · 2021Article
- A novel mutation in the mouse Pcsk1 gene showing obesity and diabetes.Mammalian genome : official journal of the International Mammalian Genome Society · 2020Article
- Genetic Obesity and Bariatric Surgery Outcome in 1014 Patients with Morbid Obesity.Obesity surgery · 2020Article
- Novel Mutations in Obesity-related Genes in Turkish Children with Non-syndromic Early Onset Severe Obesity: A Multicentre StudyJournal of clinical research in pediatric endocrinology · 2019Article
- Benefits and limitations of genome-wide association studies.Nature reviews. Genetics · 2019Review
- POMC: The Physiological Power of Hormone Processing.Physiological reviews · 2018Review
- Functional and clinical relevance of novel and knownMolecular metabolism · 2017Article
- Endoplasmic reticulum-associated degradation of the mouse PC1/3-N222D hypomorph and human PCSK1 mutations contributes to obesity.International journal of obesity (2005) · 2016Article
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Authors and funding
11 authors at 6 institutions in 2 countries.
Funding
Abstract
backgroundA 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.
methodsThrough 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.
resultsA 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.
conclusionsWe 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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