In its 125th anniversary edition several years ago, the journal Science identified “What triggers puberty?” as one of the top 100 questions for researchers over the next quarter century. A recent advance in understanding what happens when puberty goes awry has now illuminated the stimulus for the transition from childhood to adolescence.
Under normal conditions, puberty begins in girls between ages 8 and 13 and ages 9 and 14 in boys. However, in a small population of children, mostly girls, it is initiated earlier. Gonadotropin-dependent precocious puberty results from premature activation of the hypothalamic-pituitary-gonadal axis, which is responsible for the appearance of secondary sexual characteristics, accelerated growth, and ultimately the capacity for fertility. These changes in younger children can pose significant physical and emotional challenges.
“Precocious puberty is an interesting disorder to look at because, to date, there has not been any genetic cause identified. Although there were other genes implicated in failure of puberty, there had not been any for early puberty,” explained Ursula Kaiser, HMS associate professor of medicine at Brigham and Women’s Hospital. In the Feb. 14 New England Journal of Medicine, Kaiser and her colleagues report a study linking precocious puberty to an activating mutation in a G protein–coupled receptor, GPR54; the work was a collaboration with Ana Claudia Latronico and her lab at São Paulo University Medical School in Brazil.
GPR54 activation by its ligand kisspeptin turns on gonadotropin-releasing hormone (GnRH) secretion in the hypothalamus, causing the release of hormones that induce puberty. Based on previous studies reporting loss-of-function mutations in GPR54 among patients who failed to undergo puberty, the investigators hypothesized that a gain-of-function mutation could contribute to premature GnRH release, causing central precocious puberty. The team analyzed DNA isolated from 53 unrelated patients with the condition and 150 adults who underwent normal puberty. The results revealed a single activating mutation in GPR54, Arg386Pro, identified in an 8-year-old girl who displayed signs of puberty at 7.
To study the impact of this mutation on kisspeptin-mediated signaling, the researchers evaluated monkey kidney cells expressing Arg386Pro GPR54. The mutation disrupted normal receptor desensitization, causing a prolonged activation of the downstream inositol phosphate signal.
