MGH Research Scholar Stephanie Seminara, MD, is studying the factors that trigger the onset of sexual maturation during puberty.

Role of Disordered Ubiquitination in Ataxia/Hypogonadism

Stephanie Seminara, MD
Stephanie Seminara, MD
Bob and Laura Reynolds MGH Research Scholar 2014-2109
Physician Investigator and Unit Chief, Reproductive Endocrine Unit
Professor of Medicine, Harvard Medical School

Dr. Seminara studies the genes that control the timing of puberty and fertility in the human.

One of the central experiences of the human life is the transformation from childhood to adulthood—puberty.

Although puberty is a universal human experience, the triggers for sexual maturation have been a “black box” within reproductive biology for decades.

Although the hypothalamic hormone GnRH (gonadotropin hormone releasing hormone) has been traditionally viewed as the hypothalamic driver of the reproductive cascade, the factors that trigger GnRH neurons in the hypothalamus to awaken from their childhood quiescence and trigger the onset of sexual maturation have been difficult to elucidate.

Understanding the factors that modulate GnRH secretion from the hypothalamus can lead to novel treatments for disorders such as abnormal pubertal development, amenorrhea, and infertility.

Thus, the broad goal of Dr. Seminara’s work is to identify the factors that modulate GnRH secretion from the hypothalamus utilizing patients with congenital, idiopathic hypogonadotropic hypogonadism (GnRH deficiency, Kallmann syndrome).

In 2003, Dr. Seminara and co-workers identified mutations in the kisspeptin receptor (KISS1R, aka GPR54) in patients with hypogonadotropic hypogonadism and simultaneously demonstrated that mutant mice with deletions of the kisspeptin receptor also have absent sexual maturation and infertility.

The ligand for the kisspeptin receptor is the hypothalamic neuropeptide kisspeptin.

Dr. Seminara and her team were the first to identify nucleotide variants in patients in the gene encoding kisspeptin (KISS), pursuing of in silico, in vitro, and in vivo studies in mutant mice to explore the deleterious consequences of these variants.

Working collaboratively in laboratory models, Dr. Seminara has demonstrated that kisspeptin is the most potent physiologic stimulus of GnRH secretion identified to date.

Moreover, she has recognized that exogenous kisspeptin administration provides the first opportunity to query endogenous GnRH neurons—which are small in number and scattered across the hypothalamus–directly in the human brain.

Thus, to complete the translational research cycle, Dr. Seminara has taken her work in charting kisspeptin physiology back to the human to contribute to the development of improved diagnostic tools and effective therapies for patients with a range of reproductive disorders and place kisspeptin into its proper.

Dr. Seminara has built a multidisciplinary translational research program to explore the proper physiologic and pathophysiologic roles for kisspepitn, and other co-expressed neuropeptides, in men, women, and children.

In addition to kisspeptin, Dr. Seminara has recently discovered abnormalities in ubiquitination in patients with the combination of reproductive disease and progressive ataxia–a devastating neurodegenerative syndrome that leads to premature death in the 4th to 5th decades of life.

She and her team discovered that ubiquitination–the process of tagging proteins for degradation–is critical for the health of the cerebellum and the reproductive cell populations in the hypothalamus/pituitary.

This discovery has potential pathophysiologic links to other more common neurodegenerative diseases such as Parkinson’s disease, and may hold the promise of novel diagnostic tools and therapies for such patients.