GENETICS IN ENDOCRINOLOGY: Genetic etiologies of central precocious puberty and the role of imprinted genes

Abstract

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 the 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.

Figure 1.

Activation of the hypothalamic-pituitary-gonadal axis during pubertal onset. The hallmark of pubertal onset is pulsatile hypothalamic gonadotropin-releasing hormone (GnRH) release, likely due to increases in activators such as kisspeptin, the most potent known stimulator of GnRH secretion, produced by kisspeptin neurons in the preoptic area and in the arcuate nucleus (where they co-secrete neurokinin B and dynorphin and are hence known as KNDy neurons). Kisspeptin signals directly via kisspeptin receptors (KISS1R) on GnRH neurons to control pulsatile GnRH release, which in turn leads to release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary, with subsequent downstream activation of sex steroid production—testosterone from the testes and estrogen and progesterone from the ovaries—and gametogenesis. Genetic variants in CPP include mutations in (1) KISS1 and (2) KISS1R, affecting kisspeptin and its receptor, respectively, as well as in (3) MKRN3 and (4) DLK1, for which the mechanisms of action in the hypothalamus are still being fully elucidated.

Figure 2.

A. Imprinted genes in the Prader-Willi syndrome and Angelman syndrome regions of chromosome 15q11.2-13. B. Temple syndrome region of chromosome 14q32.2. Not drawn to scale. Maternally imprinted, paternally expressed genes are indicated in blue boxes and paternally imprinted, maternally expressed genes in red boxes. IC: imprinting center, DMR: differentially methylated regions. Adapted from (69, 102).

Figure 3.

Imprinting pattern of maternally imprinted, paternally expressed genes MKRN3 and DLK1. A. Maternal allele is imprinted, or silenced; mutant paternal allele is expressed, resulting in phenotype of central precocious puberty. B. Maternal allele is normally imprinted and normal paternal allele is expressed, resulting in normal puberty. C. Maternal allele containing mutation is imprinted; normal paternal allele is expressed, resulting in no pathologic phenotype (i.e., normal puberty). Adapted from (103).