The inherited disease Kallmann syndrome (KS) is characterized by gonadotropin-releasing hormone (GnRH) deficiency, hypogonadism, reproductive defects, and compromised olfaction. The relatively small number of patients with this disease has restricted the identification of KS-causing genes, resulting in a limited understanding of the pathobiology of KS. Using a multifaceted approach, Anna Cariboni and colleagues at University College London demonstrated that the class 3 semaphorin SEMA3E promotes survival of hypothalamic GnRH neurons. Whole exome sequencing of two brothers diagnosed with KS revealed the presence of a mutation in SEMA3E that was predicted by computer models to be deleterious for SEMA3E function. In a cell culture system, expression of KS-associated SEMA3E in GnRH neurons did not inhibit migration; however, KS-associated SEMA3E was unable to signal through the PLXND1 receptor, which promotes PI3K-dependent survival signaling, resulting in GnRH neuron apoptosis. In murine models, deletion of Sema3E, Plxnd1, or Kdr, which encodes a PLXND1 co-receptor, revealed that SEMA3E signaling is required for proper innervation of GnRH neurons into the adult median eminence. Additionally, mice with a disruption of SEMA3E signaling displayed a reduction in testes size, similar to human KS patients. In a companion Commentary, Shlomo Melmed at Cedars-Sinai Medical Center discusses the power of a combinatorial, multi-system approach to identify the functional consequences of genetic perturbations in hereditary endocrine disorders. The accompanying image shows coronal sections of the adult mouse hypothalamus and demonstrates that loss of SEMA3E (right) markedly reduces the innervation of GnRH-positive neuron projections (green) into the median eminence. Sections counterstained with DAPI (blue).
Individuals with an inherited deficiency in gonadotropin-releasing hormone (GnRH) have impaired sexual reproduction. Previous genetic linkage studies and sequencing of plausible gene candidates have identified mutations associated with inherited GnRH deficiency, but the small number of affected families and limited success in validating candidates have impeded genetic diagnoses for most patients. Using a combination of exome sequencing and computational modeling, we have identified a shared point mutation in semaphorin 3E (
Anna Cariboni, Valentina André, Sophie Chauvet, Daniele Cassatella, Kathryn Davidson, Alessia Caramello, Alessandro Fantin, Pierre Bouloux, Fanny Mann, Christiana Ruhrberg
Kallmann syndrome is an inherited deficiency of gonadotropin-releasing hormone (GnRH) that is characterized by hypogonadism with delayed or absent puberty and dysfunctional olfaction. While Kallmann syndrome–associated mutations have been identified in some sets of patients, for many of these individuals, the underlying cause remains unknown. In this issue of the