Endocrine Abstracts

The genetic aetiology of central delayed puberty is closely related to the development and function of the gonadotropin-releasing hormone (GnRH) endocrine network. GnRH is the master hormone regulating the reproductive axis and its pulsatile secretion from neurons of the mediobasal hypothalamus is crucial for puberty onset and fertility. Loss-of-function in genes in GnRH neuron pathways can lead to a phenotypic spectrum from self-limited delayed puberty (SLDP) to partial or complete hypogonadotropic hypogonadism (HH). Neurodevelopmental disorders such as autism and ADHD are increasingly being recognised as a shared trait with central delayed puberty and may be due to a common aetiology. We identified the Bone morphogenetic protein/retinoic acid inducible neural-specific 2 (BRINP2) gene as a candidate of interest, as it was found to be significantly upregulated during GnRH neuronal development in transcriptomic analyses and expressed in key hypothalamic nuclei. Whole exome sequencing (WES) data from 180 UK cohort probands with DP demonstrated potentially pathogenic rare coding variants in BRINP2 in probands with either SLDP or partial HH. Probands were noted to have additional phenotypes of autism, ADHD and obesity. In collaboration with the international DPGen consortium, WES data from a further 233 probands with SLDP were examined and 3 further variants of interest in BRINP2 were identified. These 7 variants are all rare or ultra-rare and are predicted to be pathogenic by in silico tools including CADD, REVEL and Primate AI. Protein expression of the p.I629V mutant was strongly reduced as compared to reference protein. BRINP2 has been shown to inhibit neuronal cell proliferation by negative regulation of cell cycle transition and to be up-regulated by estradiol. Variants in this gene have been previously associated with autism in an epidemiological study. Brinp2 knockout mice show hyperactive behaviour representative of human attention-deficit hyperactivity disorder, but pubertal timing has not been assessed. Thus, BRINP2 is a novel candidate gene for the aetiology of central delayed puberty with associated neurodevelopmental phenotypes. We have investigated the role of BRINP2 in GnRH biology via wildtype and mutant protein expression and sub-cellular localization, as well as gene expression in mouse hypothalamic tissue across development.