TCF12 haploinsufficiency causes autosomal dominant Kallmann syndrome and reveals network-level interactions between causal loci

Hum Mol Genet. 2020 Aug 11;29(14):2435-2450. doi: 10.1093/hmg/ddaa120.


Dysfunction of the gonadotropin-releasing hormone (GnRH) axis causes a range of reproductive phenotypes resulting from defects in the specification, migration and/or function of GnRH neurons. To identify additional molecular components of this system, we initiated a systematic genetic interrogation of families with isolated GnRH deficiency (IGD). Here, we report 13 families (12 autosomal dominant and one autosomal recessive) with an anosmic form of IGD (Kallmann syndrome) with loss-of-function mutations in TCF12, a locus also known to cause syndromic and non-syndromic craniosynostosis. We show that loss of tcf12 in zebrafish larvae perturbs GnRH neuronal patterning with concomitant attenuation of the orthologous expression of tcf3a/b, encoding a binding partner of TCF12, and stub1, a gene that is both mutated in other syndromic forms of IGD and maps to a TCF12 affinity network. Finally, we report that restored STUB1 mRNA rescues loss of tcf12 in vivo. Our data extend the mutational landscape of IGD, highlight the genetic links between craniofacial patterning and GnRH dysfunction and begin to assemble the functional network that regulates the development of the GnRH axis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Disease Models, Animal
  • Female
  • Genes, Dominant / genetics
  • Gonadotropin-Releasing Hormone / deficiency
  • Gonadotropin-Releasing Hormone / genetics*
  • Haploinsufficiency / genetics
  • Humans
  • Kallmann Syndrome / genetics*
  • Kallmann Syndrome / pathology
  • Male
  • Middle Aged
  • Mutation / genetics
  • Neurons / metabolism
  • Neurons / pathology
  • Phenotype
  • Ubiquitin-Protein Ligases / genetics*
  • Zebrafish / genetics
  • Zebrafish Proteins / genetics*


  • Basic Helix-Loop-Helix Transcription Factors
  • Zebrafish Proteins
  • TCF12 protein, human
  • Gonadotropin-Releasing Hormone
  • Ubiquitin-Protein Ligases
  • stub1 protein, zebrafish