Sexual Precocity - Genetic Bases of Central Precocious Puberty and Autonomous Gonadal Activation
Sexual Precocity - Genetic Bases of Central Precocious Puberty and Autonomous Gonadal Activation
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DOI：
10.1159/000438874
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发表时间：
2016-01-01
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影响因子：
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通讯作者：
Latronico, Ana Claudia
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作者：
Macedo, Delanie Bulcao;Gontijo Silveira, Leticia Ferreira;Latronico, Ana Claudia
性早熟通常被定义为8岁以下的女孩和9岁以下的男孩出现第二性特征。引发人类青春期的潜在因素的发现是生殖生物学的核心奥秘之一。几种方法，包括候选基因的突变分析，大规模的全基因组关联研究，和（最近）全外显子组测序，已被执行，试图确定新的遗传因素，调节人类下丘脑-垂体-性腺轴，导致过早的性发育。在过去的二十年中，已经确定自主性腺激活可以由编码G蛋白偶联受体信号转导必需元件的基因的体细胞（GNAS）或种系（LHCGR）激活突变引起，分别导致McCune-Albright综合征和睾丸中毒症的外周性早熟。最近，促性腺激素释放激素分泌的兴奋性（KISS 1/KISS 1 R）和抑制性（MKRN 3）调节剂的显性激活和失活突变分别与中枢性性早熟表型相关。事实上，MKRN 3（位于染色体15 q的母体印记基因）的功能缺失突变目前是不同地理来源家庭中诊断的中枢性性早熟的常见原因。在这里，我们回顾了已知的中枢性和外周性早熟的遗传缺陷。
Precocious puberty has been classically defined as the onset of sexual secondary characteristics in girls younger than 8 years and in boys younger than 9 years. The discovery of potential factors which trigger human puberty is one of the central mysteries of reproductive biology. Several approaches, including mutational analysis of candidate genes, large-scale genome-wide association studies, and (more recently) whole-exome sequencing, have been performed in attempt to identify novel genetic factors that modulate the human hypothalamic-pituitary-gonadal axis, resulting in premature sexual development. In the last two decades, it has been well established that autonomous gonadal activation can be caused by somatic (GNAS) or germline (LHCGR)-activating mutations of genes that encode essential elements for signal transduction of G protein-coupled receptors, resulting in peripheral precocious puberty in McCune-Albright syndrome and testotoxicosis, respectively. More recently, dominant activating and inactivating mutations of excitatory (KISS1/ KISS1 R) and inhibitory (MKRN3) modulators of gonadotropin-releasing hormone secretion, respectively, were associated with central precocious puberty phenotype. Indeed, loss-of-function mutations of MKRN3, a maternal imprinted gene located at chromosome 15q, currently represent a frequent cause of central precocious puberty diagnosed in families from distinct geographic origins. Here, we review the known genetic defects in central and peripheral precocious puberty.