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 hypothalamicpituitary-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.

Neuron-derived neurotrophic factor is mutated in congenital hypogonadotropic hypogonadism

“…Importantly, about half of persons with CHH do not carry mutations in the known CHH-associated genes. 3 Historically, cytogenetics, [41][42][43][44][45] linkage studies, 46,47 homozygosity mapping, 48 candidate gene approaches, 1,49 and other strategies have been used for the dis- 16 Limitations of the study included a small population size and an inability to detect significant associations to most of the known CHH-related genes. Our current strategy combined collapsed gene-based burden testing with a targeted gene population (FN3 superfamily).…”

Psychological Aspects of Congenital Hypogonadotropic Hypogonadism

“…In parallel to the clinical heterogeneity of CHH, the molecular basis is likewise diverse and complex (4). Inheritance patterns include X-linked, autosomal recessive, autosomal dominant, as well as digenic and oligogenic forms (5).…”

Snow White and the Seven Dwarfs: a fairytale for endocrinologists

“…Mutations in many genes can cause HH, and some of these genes are also implicated in CPHD (among them, CHD7, PROKR2, WDR11, FGFR1, and FGF8). In humans, a differentiating diagnosis between PROP1 and POU1F1 patients can be the presence or absence of gonadotropin deficiency, respectively, in addition to low GH, TSH, and PRL (46). In our 'study group', the candidate genes related to the phenotypic characteristics are PROP1 (47,48).…”