ZFIN ID: ZDB-PUB-200706-3
TCF12 haploinsufficiency causes autosomal dominant Kallmann syndrome and reveals network-level interactions between causal loci
Davis, E.E., Balasubramanian, R., Kupchinsky, Z.A., Keefe, D.L., Plummer, L., Khan, K., Meczekalski, B., Heath, K.E., Lopez-Gonzalez, V., Ballesta-Martinez, M.J., Margabanthu, G., Price, S., Greening, J., Brauner, R., Valenzuela, I., Cusco, I., Fernandez-Alvarez, P., Wierman, M.E., Li, T., Lage, K., Barroso, P.S., Chan, Y.M., Crowley, W.F., Katsanis, N.
Date: 2020
Source: Human molecular genetics   29(14): 2435-2450 (Journal)
Registered Authors: Davis, Erica, Katsanis, Nicholas
Keywords: none
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*
PubMed: 32620954 Full text @ Hum. Mol. Genet.
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ABSTRACT
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 gonadotropin-releasing hormone (GnRH) deficiency (IGD). Here we report thirteen families (twelve autosomal dominant, and one autosomal recessive) with an anosmic form of IGD (Kallmann syndrome; KS) 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.
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