In addition to kisspeptin, Dr. Seminara has discovered other novel genetic pathways that affect the hypothalamic modulation of GnRH secretion. Most patients with hypogonadotropic hypogonadism who receive hormone treatment are able to lead otherwise normal lives. However, a rare subset of hypogonadotropic patients have a more complex disorder known as the Gordon Holmes syndrome which is a devastating neurodegenerative disease characterized by the simultaneous occurrence of cerebellar ataxia and reproductive failure. These patients progress inexorably with marked volume loss of the brain (most notably in the cerebellum) to death in the 4 or 5th decade of life. Dr. Seminara began characterizing the reproductive endocrine phenotypes of patients with Gordon Holmes syndrome, first describing marked phenotypic variability in gonadotropin secretory defects in the absence of other pituitary endocrinopathies. Intrigued by the seemingly selective vulnerability of the cerebellum and the pituitary gonadotropes to neurodegeneration, Dr. Seminara established an international, multi-center, and interdisciplinary collaboration to uncover the pathophysiology underlying this devastating disorder.
After 10 years of effort, Dr. Seminara 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. Dr. Seminara and her collaborators identified novel homozygous mutations in RNF216, and OTUD4 which encode an E3 ubiquitin ligase and a deubiquitinase, respectively, in all three affected siblings of a kindred with Gordon Holmes syndrome. Inhibition of either RNF216 or OTUD4 in zebrafish produced cerebellar hypoplasia, microphthalmia, and small optic tecta, with simultaneous knockdown of both genes resulting in more severe phenotypes (epistasis).
Structural similarities exist between RNF216 and parkin, another E3 ubiquitin ligase mutated in a recessive form of Parkinson disease. Surviving hippocampal neurons from the brain of a deceased patient contained ubiquitin-immunoreactive intranuclear inclusions, indicating possible similarities between RNF216-associated neurodegeneration and not only Parkinson’s but also other neurodegenerative disorders in which protein aggregates are found. Notably, all patients with RNF216 mutations had dementia, a feature not previously described in Gordon Holmes syndrome.
The findings of Dr. Seminara and her team are the first to link disordered ubiquitination to neurodegenerative disease and reproductive endocrine dysfunction. Building upon her prior experience in genetics and physiology in mouse and human models, Dr. Seminara has established a multi-disciplinary international consortium of investigators to explore the genetics of Gordon Holmes syndrome in multiple in vivo models, as well as identifying the upstream regulators and downstream targets of the genes/proteins identified to date. This consortium has already identified severe loss of function mutations in another E3 ligase, STUB1, which encodes the CHIP protein, in an Asian patient with Gordon Holmes syndrome.