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.

中文翻译：

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TCF12 单倍体不足导致常染色体显性卡尔曼综合征，并揭示因果位点之间的网络级相互作用。

促性腺激素释放激素 (GnRH) 轴的功能障碍会导致一系列生殖表型，这些表型是由 GnRH 神经元的规范、迁移和/或功能缺陷引起的。为了确定该系统的其他分子成分，我们对孤立性 GnRH 缺乏症 (IGD) 的家庭进行了系统的遗传调查。在这里，我们报告13个家庭（12常染色体显性遗传和常染色体一个隐性）与IGD（卡尔曼综合征）的嗅觉缺失形式丧失功能的突变在TCF12，轨迹也已知会导致综合征和非综合征性颅缝早闭。我们表明，斑马鱼幼虫中tcf12 的缺失扰乱了 GnRH 神经元模式，同时减弱了tcf3a/b的直系同源表达，编码 TCF12 的结合配偶体，以及stub1，一种在其他 IGD 综合征形式中发生突变并映射到 TCF12 亲和网络的基因。最后，我们报告恢复的STUB1 mRNA在体内挽救了tcf12 的丢失。我们的数据扩展了 IGD 的突变景观，突出了颅面图案和 GnRH 功能障碍之间的遗传联系，并开始组装调节 GnRH 轴发育的功能网络。