GENETICS IN ENDOCRINOLOGY: Genetic etiologies of central precocious puberty and the role of imprinted genes.
GENETICS IN ENDOCRINOLOGY: Genetic etiologies of central precocious puberty and the role of imprinted genes.
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DOI：
10.1530/eje-20-0103
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发表时间：
2020-10
影响因子：
5.8
通讯作者：
Kaiser UB
中科院分区：
文献类型：
--
作者：
Roberts SA;Kaiser UB
青春期的时间是由遗传、环境、营养和表观遗传因素的复杂相互作用所调节的。确定正常青春期时间的标准，以及性早熟的定义，是根据已发表的人口研究发展而来的。遗传对青春期时间影响的重要性得到了家族性青春期时间和双胞胎研究的支持。与许多与促性腺功能减退症相关的单基因原因相比，只有四种单基因原因被描述为中枢性性早熟（CPP）。Makorin无名指蛋白3 （MKRN3）是praper - willi综合征位点内15号染色体上的母体印迹基因，其功能缺失突变是CPP最常见的遗传原因。最近，第二个母体印迹基因delta -样非规范Notch配体1 （DLK1）的几个突变也与CPP有关。在全基因组关联研究中，这两个基因的多态性也与月经初潮年龄有关。编码kisspeptin （KISS1）及其受体（KISS1R）的基因突变是GnRH分泌的有效激活剂，也被描述为与CPP相关，但仍然是罕见的单基因原因。CPP对儿童有短期和长期的健康影响，强调了理解导致青春期提前的机制的重要性。此外，考虑到印迹基因MKRN3和DLK1突变在青春期时间中的作用，其他印迹候选基因在青春期启动中也应被考虑。
Pubertal timing is regulated by the complex interplay of genetic, environmental, nutritional and epigenetic factors. Criteria for determining normal pubertal timing, and thus the definition of precocious puberty, have evolved based on published population studies. The significance of the genetic influence on pubertal timing is supported by familial pubertal timing and twin studies. In contrast to the many monogenic causes associated with hypogonadotropic hypogonadism, only four monogenic causes of central precocious puberty (CPP) have been described. Loss-of-function mutations in Makorin Ring Finger Protein 3 (MKRN3), a maternally imprinted gene on chromosome 15 within the Prader-Willi syndrome locus, are the most common identified genetic cause of CPP. More recently, several mutations in a second maternally imprinted gene, Delta-like noncanonical Notch ligand 1 (DLK1), have also been associated with CPP. Polymorphisms in both genes have also been associated with age of menarche in genome-wide association studies. Mutations in the genes encoding kisspeptin (KISS1) and its receptor (KISS1R), potent activators of GnRH secretion, have also been described in association with CPP, but remain rare monogenic causes. CPP has both short- and long-term health implications for children, highlighting the importance of understanding the mechanisms contributing to early puberty. Additionally, given the role of mutations in the imprinted genes MKRN3 and DLK1 in pubertal timing, other imprinted candidate genes should be considered for a role in puberty initiation.