|Publication Type||Journal Article|
|Year of Publication||2020|
|Authors||Davis, 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|
|Journal||Hum Mol Genet|
|Date Published||2020 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 Journal||Hum. Mol. Genet.|