New genes controlling human reproduction and how you find them

Abstract

The neuroendocrine control of reproduction in all mammals is governed by a hypothalamic neural network of approximately 1,500 gonadotropin releasing hormone (GnRH) secreting neurons that control activity of the reproductive axis across life. Recently, the syndrome of human GnRH deficiency, either with anosmia, termed Kallmann Syndrome (KS), or with a normal sense of smell, termed normosmic Idiopathic Hypogonadotropic Hypogonadism (nIHH), have proven important disease models that have revealed much about the abnormalities that can befall the GnRH neurons as they differentiate, migrate, form networks, mature and senesce. Mutations in several genes responsible for these highly coordinated developmental processes have thus been unearthed by the study of this prismatic disease model. This paper discusses several of the more important discoveries in this rapidly evolving field and puts them into a developmental and physiologic context.

Fig. 1

Pathway of Discovery of the GPR54 Gene, Mutations in its Sequence Leading to GnRH Deficiency in the Human, and Animal Knock-outs as Occurred in Reference . A pedigree (lower left) led to linkage (upper left) which led to demonstration of a biologic defect in the (then) candidate gene, GPR54, (upper right) which led to animal knock-outs (lower right) that demonstrated hypogonadism (lower center).

Fig. 2

GnRH Neuronal Ontogeny: A Story Told by Patients with GnRH Deficiency.