Mutations in SEMA3E underlie Kallmann syndrome. SEMA3E_Kallmann_syndrome

Inherited gonadotropin-releasing hormone (GnRH) deficiency impairs sexual reproduction. Linkage studies and sequencing of plausible candidates previously identified pathogenic gene defects, but the small size of affected families and low success-rate in validating candidates has impeded genetic diagnoses for most patients. Here, we have combined exome sequencing and computational modelling to identify a shared point mutation in the SEMA3E gene of two brothers with Kallmann syndrome (KS)-linked GnRH deficiency. Cell biological studies of GnRH neurons showed that SEMA3E triggered the PLXND1-dependent activation of PI3K-mediated survival signalling, which the patient mutation compromised. In agreement, knockout mice lacking SEMA3E or PLXND1 showed increased GnRH neuron apoptosis in the developing brain and therefore reduced innervation of the adult median eminence by GnRH-positive neurites. GnRH neuron deficiency in male mice was accompanied by impaired testes growth, a characteristic feature of KS. We have therefore identified SEMA3E as an essential gene for GnRH neuron development, uncovered a hitherto unexpected neurotrophic function for SEMA3E in the developing brain and elucidated a previously unrecognised molecular mechanism that prevents GnRH neuron deficiency.