IGSF10 mutations dysregulate gonadotropin-releasing hormone neuronal migration resulting in delayed puberty

Sasha R. Howard, Leonardo Guasti, Gerard Ruiz-Babot, Alessandra Mancini, Alessia David, Helenl Storr, Lousie A. Metherell, Michael Je Sternberg, Claudia P. Cabrera, Helen R. Warren, Michael R. Barnes, Richard Quinton, Nicolas de Roux, Jacques Young, Anne Guiochon-Mantel, Karoliina Wehkalampi, Valentina André, Yoav Gothilf, Anna Cariboni, Leo Dunkel

Research output: Contribution to journalArticlepeer-review


Early or late pubertal onset affects up to 5% of adolescents and is associated with adverse health and psychosocial outcomes. Self-limited delayed puberty (DP) segregates predominantly in an autosomal dominant pattern, but the underlying genetic background is unknown. Using exome and candidate gene sequencing, we have identified rare mutations in IGSF10 in 6 unrelated families, which resulted in intracellular retention with failure in the secretion of mutant proteins. IGSF10 mRNA was strongly expressed in embryonic nasal mesenchyme, during gonadotropin-releasing hormone (GnRH) neuronal migration to the hypothalamus. IGSF10 knockdown caused a reduced migration of immature GnRH neurons in vitro, and perturbed migration and extension of GnRH neurons in a gnrh3:EGFP zebrafish model. Additionally, loss-of-function mutations in IGSF10 were identified in hypothalamic amenorrhea patients. Our evidence strongly suggests that mutations in IGSF10 cause DP in humans, and points to a common genetic basis for conditions of functional hypogonadotropic hypogonadism (HH). While dysregulation of GnRH neuronal migration is known to cause permanent HH, this is the first time that this has been demonstrated as a causal mechanism in DP.

Original languageEnglish
Pages (from-to)626-642
Number of pages17
JournalEMBO Molecular Medicine
Issue number6
StatePublished - 1 Jun 2016


  • Delayed puberty
  • GnRH
  • Hypothalamic amenorrhea
  • Neuronal migration
  • Puberty

All Science Journal Classification (ASJC) codes

  • Molecular Medicine


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