Pioneering studies on monogenic central precocious puberty

Abstract

Pubertal timing in humans is determined by complex interactions including hormonal, metabolic, environmental, ethnic, and genetic factors. Central precocious puberty (CPP) is defined as the premature reactivation of the hypothalamic-pituitary-gonadal axis, starting before the ages of 8 and 9 years in girls and boys, respectively; familial CPP is defined by the occurrence of CPP in two or more family members. Pioneering studies have evidenced the participation of genetic factors in pubertal timing, mainly identifying genetic causes of CPP in sporadic and familial cases. In this context, rare activating mutations were identified in genes of the kisspeptin excitatory pathway (KISS1R and KISS1 mutations). More recently, loss-of-function mutations in two imprinted genes (MKRN3 and DLK1) have been identified as important causes of familial CPP, describing novel players in the modulation of the hypothalamic-pituitary-gonadal axis in physiological and pathological conditions. MKRN3 mutations are the most common cause of familial CPP, and patients with MKRN3 mutations present clinical features indistinguishable from idiopathic CPP. Meanwhile, adult patients with DLK1 mutations present high frequency of metabolic alterations (overweight/obesity, early onset type 2 diabetes and hyperlipidemia), indicating that DLK1 may be a novel link between reproduction and metabolism.

Insulin-like Growth Factor 1, but Not Insulin-Like Growth Factor-Binding Protein 3, Predicts Central Precocious Puberty in Girls 6–8 Years Old: A Retrospective Study

“…Notably, CPP is 15-20 times more common in girls, and its incidence is increasing [1,2]. The etiology of CPP in girls is predominantly idiopathic (86%) with an interaction of environmental and genetic (monogenic or polygenic) influences [3][4][5][6].…”

Enrichment analyses of diseases and pathways associated with precocious puberty using PrecocityDB

“…The highest number of SNPs associated with PP was reported for MKRN3 (Makorin ring finger protein 3) followed by LHCGR (luteinizing hormone (LH)/choriogonadotropin receptor gene) , KISS1 (Kisspeptin) , KISS1R (Kisspeptin receptor) , and LIN28B (Lin-28 Homolog B) . MKRN3 gene is the most widely studied gene for its association with precocious puberty 30 . It has ubiqutin protein ligase activity.…”

Neuropilin‐1 expression in GnRH neurons regulates prepubertal weight gain and sexual attraction

“…In humans, while the age of onset of pubertal development is primarily thought to be driven by genetic factors (Parent et al , ; Canton et al , ; Howard & Dunkel, ), the genetic determinants of this timing and, in particular, the factors leading to central precocious puberty are largely unknown. To date, the most frequently mutated gene in pedigrees with central precocious puberty is MKRN3 (Abreu et al , ), whose hypothalamic expression decreases during postnatal development both in primates and rodents (Abreu et al , ), and whose early repression causes precocious puberty in female rats (Heras et al , ).…”