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Hum Mol Genet DOI:10.1093/hmg/ddaa120

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

Publication TypeJournal Article
Year of Publication2020
AuthorsDavis, EE, Balasubramanian, R, Kupchinsky, ZA, Keefe, DL, Plummer, L, Khan, K, Meczekalski, B, Heath, KE, Lopez-Gonzalez, V, Ballesta-Martinez, MJ, Margabanthu, G, Price, S, Greening, J, Brauner, R, Valenzuela, I, Cusco, I, Fernandez-Alvarez, P, Wierman, ME, Li, T, Lage, K, Barroso, PSales, Chan, Y-M, Crowley, WF, Katsanis, N
JournalHum Mol Genet
Date Published2020 Jul 03

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.


Alternate JournalHum. Mol. Genet.
PubMed ID32620954