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Introduction: Gonadotropin-releasing hormone (GnRH) deficiency causes hypogonadotropic hypogonadism (HH), a rare genetic disorder that impairs sexual reproduction. HH can be due to defective GnRH-secreting neuron development or function and may be associated with other clinical signs in overlapping genetic syndromes. With most of the cases being idiopathic, genetics underlying HH is still largely unknown. Objective: To assess the contribution of mutated Semaphorin 3G (SEMA3G) in the onset of a syndromic form of HH, characterized by intellectual disability and facial dysmorphic features. Method: By combining homozygosity mapping with exome sequencing, we identified a novel variant in the SEMA3G gene. We then applied mouse as a model organism to examine SEMA3Gexpression and its functional requirement in vivo. Further, we applied homology modelling in silico and cell culture assays in vitro to validate the pathogenicity of the identified gene variant. Results: We found that (i) SEMA3G is expressed along the migratory route of GnRH neurons and in the developing pituitary, (ii) SEMA3G affects GnRH neuron development, but is redundant in the adult hypothalamic-pituitary-gonadal axis, and (iii) mutated SEMA3G alters binding properties in silico and in vitro to its PlexinA receptors and attenuates its effect on the migration of immortalized GnRH neurons. Conclusion: In silico, in vitro, and in vivo models revealed that SEMA3G regulates GnRH neuron migration and that its mutation affecting receptor selectivity may be responsible for the HH-related defects.

In mammals, fertility critically depends on the pulsatile secretion of gonadotropin-releasing hormone (GnRH) by scattered hypothalamic neurons (GnRH neurons). During development, GnRH neurons originate in the nasal placode and migrate first into the nasal compartment and then through the nasal/forebrain junction, before they reach their final position in the hypothalamus. This neurodevelopmental process, which has been extensively studied in mouse models, is regulated by a plethora of factors that might control GnRH neuron migration or survival as well as the fasciculation/targeting of the olfactory/vomeronasal axons along which the GnRH neurons migrate. Defects in GnRH neuron development or release can lead to isolated GnRH deficiency, with the underlying genetic causes still being partially unknown. Recently, semaphorins and their receptors neuropilins and plexins, a large family of molecules implicated in neuronal development and plasticity, are emerging as key regulators of GnRH neuron biology and deficiency. Specifically, semaphorins have been shown to play different roles in GnRH neuron biology by regulating migration and survival during embryonic development as well as secretion in adulthood.