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

Erica E. Davis, Ravikumar Balasubramanian, Zachary A. Kupchinsky, David L. Keefe, Lacey Plummer, Kamal Khan, Blazej Meczekalski, Karen E. Heath, Vanesa Lopez-Gonzalez, Mary J. Ballesta-Martinez, Gomathi Margabanthu, Susan Price, James Greening, Raja Brauner, Irene Valenzuela, Ivon Cusco, Paula Fernandez-Alvarez, Margaret E. Wierman, Taibo Li, Kasper LagePriscila Sales Barroso, Yee Ming Chan, William F. Crowley, Nicholas Katsanis*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish (US)
Pages (from-to)2435-2450
Number of pages16
JournalHuman molecular genetics
Volume29
Issue number14
DOIs
StatePublished - Jul 15 2020

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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