UC San Diego

Idiopathic Hypogonadotropic Hypogonadism (IHH) is a genetic disorder that can lead to delayed or absent puberty, poor development of secondary sex characteristics, and infertility. This occurs because of reduced levels of Gonadotropin-Releasing Hormone (GnRH) in the Hypothalamic-Pituitary-Gonadal (HPG) axis. Surprisingly, more than 50% of patients do not know the specific mutation causing their disorder. Our collaborators conducted whole exome sequencing in IHH patients without known genetic causes for their disease. They were able to identify novel, deleterious mutations in ZIC1, a transcription factor in the cerebellum, in multiple families in the cohort. The heterozygous mutations presented here are from four unrelated families: H134Rfs*21, Y286X, E299K, and S413Y. Unfortunately, there is no current research on ZIC1 in the reproductive pathway. My goal is to identify evidence linking ZIC1 and IHH by understanding its molecular mechanisms in the reproductive pathways. First, I transfected a shRNA to knockdown endogenous ZIC1 and observed that GnRH-Luciferase expression decreased in the GT1-7 cell line. I observed that transfection in the GT1-7 cell line of three ZIC1 mutated plasmids reversed the ZIC1-mediated expression of GnRH-Luciferase, while in the GN11 cell line, two mutations induced GnRH-Luciferase. My study will allow identification of ZIC1 as a novel regulator of the HPG axis and a potential cause for IHH.