Identification of a novel gene taking role in puberty

It is currently unknown how transition from childhood to adulthood, namely puberty, is started. This study was undertaken to identify a novel gene which has a role in pubertal process. To this end, familial anosmic hypogonadotropic hypogonadism (Kallmann syndrome), which is characterized by absence of pubertal development and sense of smell, was utilized as a human disease model. Patients from 20 multiplex families who were diagnosed with Kallmann Syndrome (KS) in the department of Pediatric Endocrinology of the Cukurova University, Faculty of Medicine were recruited. After screening out the genes known to be associated with KS, 10 of these families were further investigated for responsible gene mutations with SNP-based autozygosity mapping and whole exome sequencing. Two of these families harbored potentially harmful mutations in FEZF1. Knockout mice models for this gene were previously shown to suffer from a defective embryonic GnRH neuron migration from the olfactory placode to the hypothalamus. Mutation in the first family (p.H278Y), which involves a zinc finger motif, was demonstrated to be deleterious in a heterologous expression study in HEK298 cell line. Mutation in the second family (c.651delT; A217fs13X) is predicted to result in the absence of a protein product due to Nonsense-mediated decay. These functional deficits most probably led to unsuccessful embriyonic migration of GnRH neurons, thus resulting in failure to establish hypothalamo-pituitary-gonadal axis (HPG), activation of which in the second decade of life is the basis of puberty.In conclusion, it has been shown for the first time in this study that FEZF1 is required for normal pubertal development and deleterious mutations in FEZF1 result in KS in humans. Key Words: Puberty, Kallmann syndrome, FEZF1, Gonadotropin Releasing Hormone, Hypogonadism