PLXNB1 mutations in the etiology of idiopathic hypogonadotropic hypogonadism

J Neuroendocrinol. 2022 Apr;34(4):e13103. doi: 10.1111/jne.13103. Epub 2022 Feb 16.


Idiopathic hypogonadotropic hypogonadism (IHH) comprises a group of rare genetic disorders characterized by pubertal failure caused by gonadotropin-releasing hormone (GnRH) deficiency. Genetic factors involved in semaphorin/plexin signaling have been identified in patients with IHH. PlexinB1, a member of the plexin family receptors, serves as the receptor for semaphorin 4D (Sema4D). In mice, perturbations in Sema4D/PlexinB1 signaling leads to improper GnRH development, highlighting the importance of investigating PlexinB1 mutations in IHH families. In total, 336 IHH patients (normosmic IHH, n = 293 and Kallmann syndrome, n = 43) from 290 independent families were included in the present study. Six PLXNB1 rare sequence variants (p.N361S, p.V608A, p.R636C, p.V672A, p.R1031H, and p.C1318R) are described in eight normosmic IHH patients from seven independent families. These variants were examined using bioinformatic modeling and compared to mutants reported in PLXNA1. Based on these analyses, the variant p.R1031H was assayed for alterations in cell morphology, PlexinB1 expression, and migration using a GnRH cell line and Boyden chambers. Experiments showed reduced membrane expression and impaired migration in cells expressing this variant compared to the wild-type. Our results provide clinical, genetic, molecular/cellular, and modeling evidence to implicate variants in PLXNB1 in the etiology of IHH.

Keywords: PLXNB1; hypogonadotropic hypogonadism; puberty.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Female
  • Gonadotropin-Releasing Hormone / genetics
  • Gonadotropin-Releasing Hormone / metabolism
  • Humans
  • Hypogonadism* / genetics
  • Kallmann Syndrome* / genetics
  • Male
  • Mice
  • Mutation
  • Nerve Tissue Proteins / genetics*
  • Receptors, Cell Surface / genetics*


  • Nerve Tissue Proteins
  • PLXNB1 protein, human
  • Plxnb1 protein, mouse
  • Receptors, Cell Surface
  • Gonadotropin-Releasing Hormone

Supplementary concepts

  • Idiopathic Hypogonadotropic Hypogonadism