Genetic factors in precocious puberty

Abstract

Pubertal onset is known to result from reactivation of the hypothalamic-pituitary-gonadal (HPG) axis, which is controlled by complex interactions of genetic and nongenetic factors.Most cases of precocious puberty (PP) are diagnosed as central PP (CPP), defined as premature activation of the HPG axis. The cause of CPP in most girls is not identifiable and, thus, referred to as idiopathic CPP (ICPP), whereas boys are more likely to have an organic lesion in the brain. ICPP has a genetic background, as supported by studies showing that maternal age at menarche is associated with pubertal timing in their offspring. A gain of expression in the kisspeptin gene (KISS1), gain-of-function mutation in the kisspeptin receptor gene (KISS1R), loss-of-function mutation in makorin ring finger protein 3 (MKRN3), and loss-of-function mutations in the delta-like homolog 1 gene (DLK1) have been associated with ICPP. Other genes, such as gamma-aminobutyric acid receptor subunit alpha-1 (GABRA1), lin-28 homolog B (LIN28B), neuropeptide Y (NPYR), tachykinin 3 (TAC3), and tachykinin receptor 3 (TACR3), have been implicated in the progression of ICPP, although their relationships require elucidation. Environmental and socioeconomic factors may also be correlated with ICPP. In the progression of CPP, epigenetic factors such as deoxyribonucleic acid (DNA) methylation, histone posttranslational modifications, and noncoding ribonucleic acids may mediate the relationship between genetic and environmental factors. CPP is correlated with short-and longterm adverse health outcomes, which forms the rationale for research focusing on understanding its genetic and nongenetic factors.

The Role of Genetics in Central Precocious Puberty: Confirmed and Potential Neuroendocrine Genetic and Epigenetic Contributors and Their Interactions with Endocrine Disrupting Chemicals (EDCs)

“…Although this seems promising, a smaller study of 30 girls with CPP from Denmark failed to identify any significant mutations in LIN28B (although one girl with CPP did have a missense change His199Arg in LIN28B, this variant was also detected in one of the 132 controls) [115]. These inconsistencies could potentially be explained by the small sample size or the ethnic differences in populations, and hence, warrant further evaluation [77].…”

“…Amongst other functions, the Notch pathway is involved in cell differ-entiation during embryonic development, and is also a modulator of adipogenesis [17]. Specifically, the formation of kisspeptin neurons and their later development in adulthood are dependent on the Notch pathway [77]. Although the exact mechanism of how DLK1 affects pubertal timing is still unknown, it is postulated that the negative regulatory role of DLK1 in Notch signaling may have an effect on the development of kisspeptin neurons in the hypothalamus [78,79].…”

“…In other species, deleterious effects on this gene lead to rapid physical development (i.e., deletions in the nematode Caenorhabditis elegans result in an abnormal rapid tempo of development through larval stages to adult cuticle formation), whereas gains of function lead to delays in the developmental process [113]. In humans, in addition to their better known roles in oncology, LIN28B and LET7 also play roles in embryonic stem cell preservation as well as other cell developmental processes [77].…”

Sex differences in body composition affect total airway resistance during puberty

“…Female pubertal status was dichotomized into early (1 and 2) and late (3, 4, and 5) puberty stages [ 14 ]. Pubertal status in males was assessed using log-substituted testosterone levels [ 15 ].…”

The role of Kisspeptin signaling in Oocyte maturation

“…Development of precocious puberty has been linked to hypothalamic KP signaling ( 158 ). An aberrant gain of KP expression or KPR signaling may lead to precocious puberty ( 159 ).…”