Heterozygous mutations causing partial prohormone convertase 1 deficiency contribute to human obesity.
Heterozygous mutations causing partial prohormone convertase 1 deficiency contribute to human obesity.
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Creemers JW;Choquet H;Stijnen P;Vatin V;Pigeyre M;Beckers S;Meulemans S;Than ME;Yengo L;Tauber M;Balkau B;Elliott P;Jarvelin MR;Van Hul W;Van Gaal L;Horber F;Pattou F;Froguel P;Meyre D
编码前蛋白转化酶1/3（PC 1/3）的PCSK 1基因的突变导致隐性单基因早发性肥胖。频繁的编码变异适度损害PC 1/3功能，轻度增加普通肥胖的风险。本研究的目的是确定罕见的功能性PCSK 1突变对肥胖的贡献。对845名非血缘关系的极度肥胖欧洲人的PCSK 1外显子进行测序。8个新的非同义PCSK 1突变被确定，所有杂合子。7个突变对细胞系中PC 1/3的成熟或酶活性具有有害影响。有趣的是，这些新突变中的五个，先前描述的常见变体之一（N221 D），以及在肥胖小鼠模型中发现的突变（N222 D），影响结构钙结合位点Ca-1处或附近的残基。在6，233名肥胖和6，274名消瘦的欧洲成年人和儿童中评估了新发现的突变的患病率，结果显示，导致部分PCSK 1缺乏的任何这些突变的携带者患肥胖症的风险比野生型携带者高8.7倍。这些结果提供了PCSK 1基因突变杂合子携带者肥胖风险增加的第一个证据。此外，导致部分PCSK 1缺陷的突变存在于0.83%的极端肥胖表型中。
Null mutations in the PCSK1 gene, encoding the proprotein convertase 1/3 (PC1/3), cause recessive monogenic early onset obesity. Frequent coding variants that modestly impair PC1/3 function mildly increase the risk for common obesity. The aim of this study was to determine the contribution of rare functional PCSK1 mutations to obesity. PCSK1 exons were sequenced in 845 nonconsanguineous extremely obese Europeans. Eight novel nonsynonymous PCSK1 mutations were identified, all heterozygous. Seven mutations had a deleterious effect on either the maturation or the enzymatic activity of PC1/3 in cell lines. Of interest, five of these novel mutations, one of the previously described frequent variants (N221D), and the mutation found in an obese mouse model (N222D), affect residues at or near the structural calcium binding site Ca-1. The prevalence of the newly identified mutations was assessed in 6,233 obese and 6,274 lean European adults and children, which showed that carriers of any of these mutations causing partial PCSK1 deficiency had an 8.7-fold higher risk to be obese than wild-type carriers. These results provide the first evidence of an increased risk of obesity in heterozygous carriers of mutations in the PCSK1 gene. Furthermore, mutations causing partial PCSK1 deficiency are present in 0.83% of extreme obesity phenotypes.