ESPE 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 pulsatile release of GnRH. Defective GnRH neuron development or action may lead to GnRH deficiency (GD) which is characterized by absent or delayed puberty. Several GD causative genes have been identified so far, but half of the cases are still idiopathic. The employment of complementary research approaches may be useful to identify additional genes implicated in GD pathogenesis. Here, we combined the transcriptomic analysis of primary and immortalized GnRH neurons with whole 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 patients with severe delayed puberty and autistic traits. We demonstrated that NLGN3 is enriched in GnRH neurons at late developmental stages and its overexpression in a model of immortalized GnRH neurons promoted neurite extension. Complementary to this finding, identified NLGN3 mutations resulted in prematurely truncated proteins which are retained in the endoplasmic reticulum preventing formation of cell protrusions. 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 as NLGN3, an autism-linked gene that we found for the first time associated with GD. These data may also suggest the existence of biological or clinical links between reproductive defects and neurodevelopmental disorders.