ESPE Abstracts

Studies of patients with hypogonadotropic hypogonadism or delayed puberty have identified genes whose encoded proteins are important for GnRH neuronal development and/or stimulation of GnRH secretion to trigger puberty onset. Notably, the neuropeptides, kisspeptin and neurokinin B, produced in hypothalamic neurons upstream of GnRH neurons, were identified as key activators of pulsatile GnRH secretion. However, the mechanisms restraining GnRH secretion during childhood to prevent premature activation of the hypothalamic-pituitary-gonadal axis remained elusive. We identified loss-of-function mutations in Makorin ring finger protein 3 (MKRN3), now recognized as the most common genetic cause of central precocious puberty, implicating this protein as an inhibitor of puberty initiation. Consistent with this inhibitory role, Mkrn3 is highly expressed in the mouse hypothalamus, with marked declines prior to puberty onset. Our recent insights into the mechanisms of action of Mkrn3 to regulate pubertal timing, leveraging in vivo studies in mice and in vitro studies in cell models, will be presented.