Central precocious puberty caused by mutations in the imprinted gene MKRN3.
Central precocious puberty caused by mutations in the imprinted gene MKRN3.
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由印记基因MKRN3突变引起的中央早熟青春期。
DOI：
10.1056/nejmoa1302160
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发表时间：
2013-06-27
期刊：
影响因子：
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通讯作者：
Kaiser UB
中科院分区：
文献类型：
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作者：
Abreu AP;Dauber A;Macedo DB;Noel SD;Brito VN;Gill JC;Cukier P;Thompson IR;Navarro VM;Gagliardi PC;Rodrigues T;Kochi C;Longui CA;Beckers D;de Zegher F;Montenegro LR;Mendonca BB;Carroll RS;Hirschhorn JN;Latronico AC;Kaiser UB
青春期的开始首先被检测为促性腺激素释放激素（GnRH）脉冲式分泌的增加。下丘脑-垂体-性腺轴的早期激活导致中枢性早熟。青春期发育的时间部分由遗传因素驱动，但只有少数罕见的与中枢性早熟相关的分子缺陷已被确定。我们对15个中枢性性早熟家系的40名成员进行了全外显子组测序。用桑格测序确认候选变体。我们还进行了定量实时聚合酶链反应测定，以确定信使RNA（mRNA）在不同年龄的小鼠下丘脑的水平。我们在15个家族中的5个家族中发现了4个编码Makorin环指蛋白3的基因MKRN3的新杂合突变;男女都受到影响。这些突变包括三个移码突变，预测编码截短的蛋白质，和一个错义突变，预测破坏蛋白质功能。MKRN3是位于Prader-Willi综合征关键区域（染色体15q11-q13）的父系表达的印记基因。所有受影响的人都从他们的父亲那里继承了突变，这一发现表明与印记基因预期的遗传模式完全分离。Mkrn3 mRNA水平在青春期前小鼠的弓状核中较高，在青春期前立即下降，并在青春期后保持较低。MKRN3缺乏导致人类中枢性性早熟。（由美国国立卫生研究院和其他机构资助。
The onset of puberty is first detected as an increase in pulsatile secretion of gonadotropin-releasing hormone (GnRH). Early activation of the hypothalamic–pituitary–gonadal axis results in central precocious puberty. The timing of pubertal development is driven in part by genetic factors, but only a few, rare molecular defects associated with central precocious puberty have been identified. We performed whole-exome sequencing in 40 members of 15 families with central precocious puberty. Candidate variants were confirmed with Sanger sequencing. We also performed quantitative real-time polymerase-chain-reaction assays to determine levels of messenger RNA (mRNA) in the hypothalami of mice at different ages. We identified four novel heterozygous mutations in MKRN3, the gene encoding makorin RING-finger protein 3, in 5 of the 15 families; both sexes were affected. The mutations included three frameshift mutations, predicted to encode truncated proteins, and one missense mutation, predicted to disrupt protein function. MKRN3 is a paternally expressed, imprinted gene located in the Prader–Willi syndrome critical region (chromosome 15q11–q13). All affected persons inherited the mutations from their fathers, a finding that indicates perfect segregation with the mode of inheritance expected for an imprinted gene. Levels of Mkrn3 mRNA were high in the arcuate nucleus of prepubertal mice, decreased immediately before puberty, and remained low after puberty. Deficiency of MKRN3 causes central precocious puberty in humans. (Funded by the National Institutes of Health and others.)