SAT-167 A BAIAP3 Variant In Males With Pubertal Failure: Expression And Function In The Reproductive Axis

Abstract Disclosure: M. Akram: None. S. Wray: None. Gonadotropin releasing hormone (GnRH) neuroendocrine cells in the brain release GnRH in a pulsatile fashion at the median eminence to alter hormone secretion in gonadotropes of the pituitary and subsequently the gonads. As such, GnRH cells control reproductive function, being an integral component of the hypothalamic-pituitary-gonadal (HPG) axis. In a previous study, a mutation was identified in the BAIAP3 (brain-specific angiogenesis inhibitor I-associated protein 3) gene in a male patient that had not undergone pubertal changes. BAIAP3 has been implicated in angiogenesis, synapse formation, neuronal development, neurotransmitter release and dysregulation of BAIAP3 has been linked to neuropsychiatric disorders. In neuroendocrine and endocrine cells, BAIAP3 encodes a dense core vesicle (DCV) protein involved in recycling at the trans-Golgi network, consistent with a role in vesicle release. This study examines the expression and function of BAIAP3 in the components of the HPG axis to determine if the mutation in BAIAP3 associated with absence of puberty was in fact causal. BAIAP3 mRNA and protein was found in GnRH cells and during development correlates with maturation of peptide processing and secretion. BAIAP3 mRNA and protein was also found in the testis, localized to mature sperm. Although BAIAP3 was found in the posterior lobe of the pituitary, it was not detected in the gonadotropes in the anterior pituitary. Thus, expression patterns suggest BAIAP3 is involved in two components of the HPG axis, GnRH cells and the gonads. Stimulation of GnRH cells with KCl results in an immediate increase in BAIAP3 expression, consistent with a role in vesicle recycling. Future work will focus on delineating the role of BAIAP3 in spermatogenesis using testis markers. Moreover, the number and function of GnRH cells and spermatogenesis in BAIAP3 KO mice models will be examined. Finally, using an in vitro model known to maintain primary GnRH neuroendocrine cells, we are knocking down BAIAP3 and determining changes in expression of DCV markers, as well as secretion of GnRH. Together these experiments will uncover the role of BAIAP3 in two components of the HPG axis and how disruption of this gene can lead to delayed or absent puberty. Presentation: Saturday, July 12, 2025