Loss-of-function variants in SEMA3F and PLXNA3 encoding semaphorin-3F and its receptor plexin-A3 respectively cause idiopathic hypogonadotropic hypogonadism

Genet Med. 2021 Jun;23(6):1008-1016. doi: 10.1038/s41436-020-01087-5. Epub 2021 Jan 25.


Purpose: Idiopathic hypogonadotropic hypogonadism (IHH) is characterized by absent puberty and subsequent infertility due to gonadotropin-releasing hormone (GnRH) deficiency. IHH can be accompanied by normal or compromised olfaction (Kallmann syndrome). Several semaphorins are known potent modulators of GnRH, olfactory, and vomeronasal system development. In this study, we investigated the role of Semaphorin-3F signaling in the etiology of IHH.

Methods: We screened 216 IHH patients by exome sequencing. We transiently transfected HEK293T cells with plasmids encoding wild type (WT) or corresponding variants to investigate the functional consequences. We performed fluorescent IHC to assess SEMA3F and PLXNA3 expression both in the nasal region and at the nasal/forebrain junction during the early human fetal development.

Results: We identified ten rare missense variants in SEMA3F and PLXNA3 in 15 patients from 11 independent families. Most of these variants were predicted to be deleterious by functional assays. SEMA3F and PLXNA3 are both expressed along the olfactory nerve and intracranial projection of the vomeronasal nerve/terminal nerve. PLXNA1-A3 are expressed in the early migratory GnRH neurons.

Conclusion: SEMA3F signaling through PLXNA1-A3 is involved in the guidance of GnRH neurons and of olfactory and vomeronasal nerve fibers in humans. Overall, our findings suggest that Semaphorin-3F signaling insufficiency contributes to the pathogenesis of IHH.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Adhesion Molecules
  • HEK293 Cells
  • Humans
  • Hypogonadism* / genetics
  • Membrane Proteins
  • Nerve Tissue Proteins / genetics
  • Receptors, Cell Surface
  • Semaphorins*


  • Cell Adhesion Molecules
  • Membrane Proteins
  • Nerve Tissue Proteins
  • PLXNA3 protein, human
  • Receptors, Cell Surface
  • SEMA3F protein, human
  • Semaphorins
  • plexin

Supplementary concepts

  • Idiopathic Hypogonadotropic Hypogonadism