Contributions of Function-Altering Variants in Genes Implicated in Pubertal Timing and Body Mass for Self-Limited Delayed Puberty.
Contributions of Function-Altering Variants in Genes Implicated in Pubertal Timing and Body Mass for Self-Limited Delayed Puberty.
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DOI：
10.1210/jc.2017-02147
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发表时间：
2018-02-01
期刊：
影响因子：
--
通讯作者：
Dunkel L
中科院分区：
文献类型：
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作者：
Howard SR;Guasti L;Poliandri A;David A;Cabrera CP;Barnes MR;Wehkalampi K;O'Rahilly S;Aiken CE;Coll AP;Ma M;Rimmington D;Yeo GSH;Dunkel L
自限性青春期延迟（DP）通常与身体成熟延迟有关，但尽管具有高度遗传性，但因果遗传因素仍然难以捉摸。对青春期时间的全基因组关联研究已经确定了女性初潮年龄和男性声音中断的多个位点，特别是在控制能量平衡的途径中。我们试图评估这些基因中罕见变异对家族性DP表型的贡献。我们对来自我们独特的家族性自限性DP队列的67个家系（125名DP患者和35名未受影响的对照）进行了全外显子组测序。使用全外显子组测序过滤管道，鉴定了一个候选基因[脂肪量和肥胖相关基因（FTO）]。进行了计算机模拟、体外和小鼠模型研究，以研究FTO变体的致病性和FTO+/−小鼠的青春期时间。我们通过对283个基因中初潮位点年龄的全基因组关联研究，确定了连锁不平衡基因中潜在致病的罕见变异。其中，有五个基因与控制体重有关。在对性状分离进行过滤后，保留了一个候选物FTO。在来自三个家庭的14名受影响的个体中发现的两种FTO变体也与这些DP患者的消瘦有关。一种变体（p.Leu44Val）在体外表现出改变的突变蛋白的去甲基化活性。Fto+/−小鼠显示青春期开始时间显著延迟（P < 0.05）。与一般人群的体重和青春期时间有关的基因突变可能导致自限性DP的发病机制。我们评估了在一般人群中对青春期发育时间和体重调节重要的基因的罕见变异对家族性青春期延迟表型的贡献。
Self-limited delayed puberty (DP) is often associated with a delay in physical maturation, but although highly heritable the causal genetic factors remain elusive. Genome-wide association studies of the timing of puberty have identified multiple loci for age at menarche in females and voice break in males, particularly in pathways controlling energy balance. We sought to assess the contribution of rare variants in such genes to the phenotype of familial DP. We performed whole-exome sequencing in 67 pedigrees (125 individuals with DP and 35 unaffected controls) from our unique cohort of familial self-limited DP. Using a whole-exome sequencing filtering pipeline one candidate gene [fat mass and obesity–associated gene (FTO)] was identified. In silico, in vitro, and mouse model studies were performed to investigate the pathogenicity of FTO variants and timing of puberty in FTO+/− mice. We identified potentially pathogenic, rare variants in genes in linkage disequilibrium with genome-wide association studies of age at menarche loci in 283 genes. Of these, five genes were implicated in the control of body mass. After filtering for segregation with trait, one candidate, FTO, was retained. Two FTO variants, found in 14 affected individuals from three families, were also associated with leanness in these patients with DP. One variant (p.Leu44Val) demonstrated altered demethylation activity of the mutant protein in vitro. Fto+/− mice displayed a significantly delayed timing of pubertal onset (P < 0.05). Mutations in genes implicated in body mass and timing of puberty in the general population may contribute to the pathogenesis of self-limited DP. We assessed the contribution of rare variants in genes important in the timing of puberty and body mass regulation in the general population to the phenotype of familial delayed puberty.
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FTO对于通过高脂喂养诱导瘦素耐药性是必需的。
影响因子：
8.1
作者：
Tung YC;Gulati P;Liu CH;Rimmington D;Dennis R;Ma M;Saudek V;O'Rahilly S;Coll AP;Yeo GS
通讯作者：
Yeo GS
影响因子：
3.7
作者：
McTaggart JS;Lee S;Iberl M;Church C;Cox RD;Ashcroft FM
通讯作者：
Ashcroft FM
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
16.6
作者：
Day FR;Bulik-Sullivan B;Hinds DA;Finucane HK;Murabito JM;Tung JY;Ong KK;Perry JRB
通讯作者：
Perry JRB
影响因子：
30.8
作者：
通讯作者：
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