Endocrine Abstracts

During development, gonadotropin releasing hormone (GnRH) neurons are born in the nasal placode and migrate to the hypothalamus, where they position to regulate sexual reproduction by the pulsatile release of GnRH. Defective GnRH neuron development or action may lead to GnRH deficiency (GD) which is characterized by absent or delayed puberty (1). GD can also be present as a trait shared by several complex neurodevelopmental disorders (NDDs), such as cerebellar ataxia, developmental delay and autism spectrum disorder (ASD) (2). Interestingly, a recent register-based population study showed for the first time that patients with GD have increased risk for being diagnosed with ASD or other NDDs, but the underlying genetic correlation is unknown (3). Although more than 20 genes have been associated to GD pathogenesis (4), half of the cases are still idiopathic, suggesting the need of novel experimental approaches to identify the elusive genes. Here, we combined the transcriptomic analysis of primary and immortalized GnRH neurons with exome sequencing data from GD patients to identify novel candidate genes. As a proof-of-principle, we identified pathogenic variants in the autism-linked Neuroligin 3 (NLGN3) gene in two unrelated patients sharing GD and ASD. We demonstrated that NLGN3 is enriched in GnRH neurons at late developmental stages and its overexpression in a model of immortalized GnRH neurons (GN11 cells) promoted neurite extension. Further, the two identified NLGN3 mutations, which are both loss-of-function, formed prematurely truncated proteins that were retained in the endoplasmic reticulum thus preventing cell protrusion formation in GN11 cells. Overall, our results highlighted how the combination of gene expression and exome sequencing data is a reliable approach to identify novel candidate gene for GD such a NLGN3, an autism-linked gene that we found for the first time associated to GD.

References: 1. Boehm U, Bouloux P-M, Dattani MT, et al. Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2015;11(9):547-564. doi:10.1038/nrendo.2015.112 2. de Roux N, Carel J-C, Léger J. Congenital Hypogonadotropic Hypogonadism: A Trait Shared by Several Complex Neurodevelopmental Disorders. In: Endocrine Development. Vol 29.; 2016:72-86. doi:10.1159/000438875 3. Ohlsson Gotby V, Söder O, Frisén L, et al. Hypogonadotrophic hypogonadism, delayed puberty and risk for neurodevelopmental disorders. J Neuroendocrinol. 2019;31(11). doi:10.1111/jne.12803 4. Oleari R, Massa V, Cariboni A, Lettieri A. The Differential Roles for Neurodevelopmental and Neuroendocrine Genes in Shaping GnRH Neuron Physiology and Deficiency. Int J Mol Sci. 2021;22(17):9425. doi:10.3390/ijms22179425