ESPE Abstracts

Gonadotropin releasing hormone (GnRH) neurons embryonically originate in nasal placode and migrate to hypothalamus, where they release GnRH to control reproduction. Defective GnRH neuron development or function leads to GnRH deficiency (GD), which is often associated to neurodevelopmental and neurological syndromes, including epilepsy, ataxia, intellectual disabilities and deafness. In addition, a register-based study showed correlation between delayed puberty and neurodevelopmental disorders. Notably, half of GD cases are still idiopathic and the discovery of novel genetic determinants might be hidden by co-occurrence of GD with severe symptoms in complex diseases. Complementary research approaches may be useful to identify additional genes implicated in the pathogenesis of GD syndromic forms. First, by combining transcriptomic analysis of primary and immortalized GnRH neurons with exome sequencing data from GD patients, we identified nonsense variants in autism-linked gene Neuroligin 3 (NLGN3) in patients exhibiting GD and autistic traits. We showed that NLGN3 expression is higher in GnRH neurons at late developmental stages and demonstrated that overexpression of wildtype NLGN3 in immortalized GnRH neurons promotes neurite extension, whilst mutated forms of NLGN3 are retained in cytoplasm preventing neuritogenesis. Then, we investigated whether Heparan Sulfate 6-O Sulfotransferase 2 (HS6ST2) gene, implicated in a neurodevelopmental disorder, genetically interacts with its paralogue HS6ST1, a known GD gene. We showed Hs6st1 and Hs6st2 enrichment in the olfactory placode and that mice with combined Hs6st1/Hs6st2 deletions have impaired GnRH neuron migration due to aberrant nasal axons and fewer GnRH neurons overall. Consistently, they display increased apoptotic rate of GnRH neurons and defective binding of pro-survival signal VEGF. Overall, we highlighted how the combination of gene expression and exome sequencing data together with in vitro and in vivo models, is a reliable approach to identify novel GD candidate genes, including NLGN3 and HS6ST2, which are already involved in neurological syndromes and represent a link between reproductive and neurodevelopmental disorders.