Philippe J, Stijnen P, Meyre D, De Graeve F, Thuillier D, Delplanque J, Gyapay G, Sand O, Creemers J W, Froguel P, Bonnefond A
1] CNRS-UMR8199, Institut de Biologie de Lille, Lille Pasteur Institute, Lille, France [2] Lille 2 University, Lille, France [3] European Genomic Institute for Diabetes (EGID), Lille, France.
Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven, Belgium.
Int J Obes (Lond). 2015 Feb;39(2):295-302. doi: 10.1038/ijo.2014.96. Epub 2014 Jun 3.
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.
相当一部分严重的家族性肥胖形式在遗传方面仍不明确。利用我们独特的多代肥胖家族队列，我们旨在评估29个常见肥胖相关基因中的罕见突变对家族性肥胖的贡献，并在这些家族中评估9种已知单基因肥胖形式的可能存在情况。
通过下一代测序，我们对来自13个法国家庭的201名参与者（75名体重正常个体、54名超重个体和72名I、II或III级肥胖个体）中涉及多基因和/或单基因肥胖形式的34个基因的编码区进行了测序。对在一个家族中鉴定出的PCSK1-p.Arg80*突变进行了体外功能分析。
在一个三代家族中发现，编码前肽的PCSK1基因（p.Arg80*）出现一种新的杂合无义变体，该前肽截短至不到14个外显子中的2个外显子，并与肥胖共分离。我们证明，这种突变抑制了PCSK1酶的活性，并且这种抑制很可能不涉及强烈的物理相互作用。此外，本研究中还鉴定出先前报道与严重肥胖相关的PCSK1-p.Asn180Ser和POMC-p.Phe144Leu这两种突变，但它们并未与肥胖共分离。最后，除了CADM2和QPCTL外，我们在常见肥胖易感基因中未发现与肥胖共分离的任何罕见突变，在CADM2和QPCTL中，我们在三名肥胖个体中分别发现了两种新变体（分别为p.Arg81His和p.Leu98Pro）。
我们首次表明，PCSK1基因中的无义突变可能由于无效等位基因编码的前肽片段的抑制特性而导致显性遗传的人类肥胖。此外，目前的家族测序设计对先前报道的突变对单基因或至少严重肥胖的贡献提出了质疑。
