Genetic discoveries are changing the ways endocrinologists envision, diagnose, and treat disease. Endocrinologists may be closet Mendelians, comfortable with major diseases that can be traced to single gene defects, but a growing body of evidence suggests that even Mendelian diseases such as isolated GnRH deficiency (IGD) are actually oligogenic or even complex genetic diseases.
“The Human Genome Project set the stage for broader, more complex models of human diseases,” said William F. Crowley, Jr, MD, Daniel K. Podolsky Professor of Medicine at Harvard Medical School and director of the NICHD Harvard Center of Excellence in Translational Research in Human Reproduction. “We are seeing that Mendelian models can exhibit significant oligogenicity and action through modifier genes that may solve some of our familiar genetic puzzles.”
Dr. Crowley explored some of the ways genetic findings have altered the direction of disease research during a plenary presentation “Discovering the Genetic Architecture of Endocrine Systems Using Human Disease Models: A Journey from Mendel to Populations” on Sunday morning. His example was isolated GnRH deficiency, long believed to be a monogenic disorder.
The normal HPG axis links the hypothalamus, pituitary, and gonads with a combination of tropic hormone drivers and steroid/peptide feedback. The entire system is controlled by GnRH neurons, a distinct population of about 1,200 neurons that act as master regulators of the HPG axis.
While GnRH dysfunction has long been recognized in diseases such as IGD, Dr. Crowley said, the Human Genome project identified the GnRH gene as unique: it has no biological backup. As Dr. Crowley noted, the first successful gene therapy was the replacement of a defective GnRH gene to treat IGD.
But the picture of IGD as a monogenic disease does not match observations of different clinical phenotypes, genetics, and developmental biology.
The picture began to clear in 2003 with the discovery of kisspeptin signaling using genetic mapping of endogamous families. The discovery of the kisspeptin signaling system and its role in initiating GnRH secretion at puberty opened a variety of new research opportunities and genetic screening products.
IGD can serve as a model that can help broaden research perspectives to recognize the oligogenicity of what might appear to be monogenic diseases, Dr. Crowley said. Recent discoveries include new “master genes” in puberty, KNDY neurons as a new regulatory mechanism for GnRH, the reversibility of IGD in adulthood and implications in treatment, the causes of adult onset IGD, heterozygous loss of function mutations in IGD genes, mutations to genes involved in GnRH stem cell precursors, and more.
“The take-home message is that the convergence of Mendelian and complex genetic approaches is producing novel, synergistic biological information,” he concluded. “The future opportunities lie in complex trait genetics and next generation sequencing tools to make the most of them.”