Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the “-Omics” Era

Abstract

The neuroendocrine regulation of reproduction is an intricate process requiring the exquisite coordination of an assortment of cellular networks, all converging on the GnRH neurons. These neurons have a complex life history, migrating mainly from the olfactory placode into the hypothalamus, where GnRH is secreted and acts as the master regulator of the hypothalamic-pituitary-gonadal axis. Much of what we know about the biology of the GnRH neurons has been aided by discoveries made using the human disease model of isolated GnRH deficiency (IGD), a family of rare Mendelian disorders that share a common failure of secretion and/or action of GnRH causing hypogonadotropic hypogonadism. Over the last 30 years, research groups around the world have been investigating the genetic basis of IGD using different strategies based on complex cases that harbor structural abnormalities or single pleiotropic genes, endogamous pedigrees, candidate gene approaches as well as pathway gene analyses. Although such traditional approaches, based on well-validated tools, have been critical to establish the field, new strategies, such as next-generation sequencing, are now providing speed and robustness, but also revealing a surprising number of variants in known IGD genes in both patients and healthy controls. Thus, before the field moves forward with new genetic tools and continues discovery efforts, we must reassess what we know about IGD genetics and prepare to hold our work to a different standard. The purpose of this review is to: 1) look back at the strategies used to discover the "known" genes implicated in the rare forms of IGD; 2) examine the strengths and weaknesses of the methodologies used to validate genetic variation; 3) substantiate the role of known genes in the pathophysiology of the disease; and 4) project forward as we embark upon a widening use of these new and powerful technologies for gene discovery. (Endocrine Reviews 36: 603-621, 2015)

Control of puberty onset and fertility by gonadotropin-releasing hormone neurons

“…Nevertheless, considerable progress has been made in defining a wide range of genetic mutations associated with IHH that either directly or indirectly influences the activity of the GnRH neuronal network 212,213 .…”

“…This syndrome arises from mutations in genes such as NELF, CHD7, KAL1, FGFR1, FGF8, WDR11, PROK2, PROKR2 and SEMA-3A that primarily alter olfactory development and, consequently, impede GnRH neuron migration from the olfactory placode into the hypothalamus 7,212,213 . Although the absence of GnRH neurons in the human hypothalamus has only been demonstrated for KAL1 mutations to date 214 , animal models indicate that other Kallmann-related mutations will probably result from the same defect 7 .…”

“…Mutations in genes such as KISS1R and GNRH alter the functioning of GnRH neurons directly, whereas defects in KISS1, TAC3, TACR3, LEP and LEPR affect other elements within the GnRH neuronal network 212,213 . The reproductive phenotypes of individuals with IHH are highly variable and it seems likely that many cases arise from oligogenic interactions between two or more affected alleles 212,215 .…”

“…Leaving aside the genetic mutations underlying Kallmann syndrome, in which failed GnRH migration is often merely a bystander effect, only a small number of critical genes has been identified among patients with normosmic IHH. The genes identified to date primarily encode proteins involved in kisspeptin, NKB and leptin signalling pathways 213,218 . Even then, patients with NKB mutations can exhibit spontaneous reproductive recovery in adulthood 219 .…”

Assessing new peptides that may be involved in the physiological regulation of the gonadal axis in humans: gonadotrophin inhibitory hormone

“…Approximately 1200 GnRH neurons reside in the arcuate‐nucleus of the mediobasal hypothalamus and secrete GnRH in a pulsatile fashion into a portal microvasculature system where the anatomic proximity to pituitary gonadotrophes allows effectual hypothalamo–pituitary signalling. Major advances identifying the genes responsible for migration of GnRH neurons from the olfactory placode into the upper diencephalon, olfactory‐bulb morphogenesis and other neurodevelopmental or neuroendocrine processes have occurred in the last two decades . In parallel, the kisspeptin–neurokinin B‐dynorphin (KNDy) neuron was identified as the upstream regulator of the GnRH neuron .…”