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Contribution du gène PCSK1 aux formes monogéniques et polygéniques d’obésité

Abstract : Four whole genome studies basing on positional cloning approach revealed a region ofchromosome 5q linked to traits related to obesity, this region contained the gene coding forthe prohormone convertase 1 named PCSK1. Pc1 mutation in mice has been associated withobesity, hyperphagia and increased metabolic efficiency. In human, PCSK1 deficiency is amonogenic form of obesity. The first case of complete PCSK1 deficiency has been identifiedin 1997 and since two other cases were discovered. Deleterious PCSK1 mutations carrierswere either homozygous or compound heterozygous and presented severe phenotypes, such asobesity, intestinal troubles and endocrine disorders. Surprisingly, the family members whowere heterozygous for these mutations appeared clinically unaffected. Overall of these studieshighlighted PCSK1 as a candidate gene for obesity.We have therefore decided to assess the contribution of PCSK1 gene to polygenicobesity risk. To assess the contribution of PCSK1 to polygenic obesity risk, we genotyped tagsingle nucleotide polymorphisms in a total of 13,659 European individuals from eightindependent case-control or family-based cohorts. The non-synonymous variants rs6232,encoding N221D, and cluster rs6234-rs6235, encoding the Q665E-S690T pair, wereconsistently associated with obesity in adults and children (P=7.27 x 10-8 and P=2.31 x 10-12,respectively). Functional analysis revealed a significant impairment of the N221D mutant onPC1/3 protein catalytic activity.In continuity of this study we decided to assess the involvement of PCSK1 gene inmonogenic obesity, knowing that only three cases of complete PCSK1 deficiency have beenreported up to now. The objectives of this study were to evaluate the prevalence of rarePCSK1 mutations contributing to human obesity and to investigate the mode of inheritance ofobesity in the context of PCSK1 deficiency. We sequenced exons of the PCSK1 gene in 845non-consanguineous extremely obese subjects of European origin and we identified eightnovel PCSK1 non-synonymous mutations in eight carriers, all heterozygous. Wecharacterized the functional consequences of the detected mutations on PC1/3 protein and wefound that 62.5% of mutations detected were predicted to be deleterious in silico and werevealed that 87.5% of mutations had an effect on the autoactivation or on the enzymaticactivity of PC1/3 in vitro. In order to estimate the degree of penetrance for the sevenpathogenic mutations, we genotyped 6,060 obese and 6,274 lean subjects. We assessed a 6-fold enrichment of these PCSK1 mutations in obese subjects (P = 0.007). We provided thefirst evidence of an increased obesity risk in heterozygous carriers of loss of functionmutations in PCSK1 gene, confirming a co-dominant mode of transmission of obesity withincomplete penetrance for this gene. The penetrance of obesity was estimated to 54.5% for108heterozygous carriers of deleterious PCSK1 mutations. Partial PCSK1 deficiency mightexplain ~ 0.83% of extreme obesity.To conclude, in addition of the syndromic forms of obesity due to a complete PCSK1deficiency, we provided the strong evidence of the contribution of common non-synonymousvariants in obesity risk and we highlighted that a partial PCSK1 deficiency is associated withan increased risk of obesity.
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Submitted on : Monday, March 14, 2011 - 12:08:16 PM
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Hélène Choquet. Contribution du gène PCSK1 aux formes monogéniques et polygéniques d’obésité. Médecine humaine et pathologie. Université du Droit et de la Santé - Lille II, 2010. Français. ⟨NNT : 2010LIL2S012⟩. ⟨tel-00576415⟩



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