Endocrine Abstracts

Gonadotropin-releasing hormone (GnRH) is the master hormone regulating the reproductive axis and its pulsatile secretion is crucial for puberty onset and fertility. Disruption in GnRH neuron development or hypothalamic function can lead to absent or delayed puberty (DP), with a phenotypic spectrum from severe DP to partial or complete Hypogonadotropic Hypogonadism (HH). We aimed to identify novel genetic etiology of severe DP by screening and identifying variants in associated genes in our cohort of patients; and ascertain the functional effects of identified variants of interest. Whole exome sequencing (WES) was performed on DNA samples from 180 probands with DP from our patient cohorts to identify potentially pathogenic novel, or rare coding variants in relevant gene pathways. Integrative analysis was performed on genomic data from human patients combined with transcriptomics analysis of rodent immortalized and primary GnRH neurons to determine novel regulators of GnRH neuronal development and function. BRINP2 was identified as a candidate gene of interest as it was found to be significantly upregulated during GnRH neuronal development in these single cell transcriptomics analyses. BRINP2 is localized to the olfactory bulb, a key site during GnRH neuron migration, and has been associated with neurodevelopmental disorders (NDD). WES analysis identified three rare predicted pathogenic variants in BRINP2 in four unrelated probands with severe DP or partial HH, in combination with NDDs. We have investigated the role of BRINP2 in GnRH biology via wildtype and mutant protein expression and sub-cellular localization, as well as tissue expression in mouse hypothalamic tissue across development.