Understanding the genetic control of puberty in the human
One of the fundamental mysteries of biology has been the genetic control of puberty in the human. High degrees of species specificity in the control of GnRH secretion, the central actor in sexual maturation, and the rarity of a discrete period of childhood quiescence independent of suckling in most animals have compounded this problem.
The clinical condition of Idiopathic Hypogonadotropic Hypogonadism, either with normosmia (nIHH)) or with anosmia (Kallmanns Syndrome [KS]), has thus emerged as an invaluable human model in this line of inquiry. IHH is an isolated GnRH deficiency combined with a demonstrable responsiveness to exogenous GnRH administration in the absence of an anatomic cause. While rare, IHH has a rich clinical and genetic heterogeneity that has enabled the elucidation of several single genes which, when mutated, create a monogenic form of delayed puberty. Via this model, the crucial roles of KAL-1 in GnRH neuronal migration, DAX-1 in hypothalamic-pituitary development, and GnRHR in gonadotrope responsiveness have been identified.
Recently, mutations in a G-coupled protein receptor (GPR54), previously unsuspected as having a role in GnRH secretion, was demonstrated to cause IHH and to be essential for normal puberty in the human as is its peptide ligand, metastin. Initially identified in IHH families, its crucial role in sexual maturation has now been confirmed in rodents and primates.
In addition, a second gene causing an autosomal dominant form of Kallmanns Syndrome has been discovered via deletional mapping studies. The gene encoding the Fibroblast Growth Factor Receptor 1 (FGFR-1) often has an accompanying skeletal phenotyping in addition to IHH signaling its presence clinically.
The clinical and genetic heterogeneity of these latter two genes as well as their implication for sexual maturation in general will be the topic of this lecture.