Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by infertility and the absence of puberty. Defects in GnRH neuron migration or altered GnRH secretion and/or action lead to a severe gonadotropin-releasing hormone (GnRH) deficiency. Given the close developmental association of GnRH neurons with the olfactory primary axons, CHH is often associated with anosmia or hyposmia, in which case it is defined as Kallmann syndrome (KS). The genetics of CHH are heterogeneous, and >40 genes are involved either alone or in combination. Several CHH-related genes controlling GnRH ontogeny encode proteins containing fibronectin-3 (FN3) domains, which are important for brain and neural development. Therefore, we hypothesized that defects in other FN3-superfamily genes would underlie CHH. Next-generation sequencing was performed for 240 CHH unrelated probands and filtered for rare, protein-truncating variants (PTVs) in FN3-superfamily genes. Compared to gnomAD controls the CHH cohort was statistically enriched for PTVs in neuron-derived neurotrophic factor (NDNF) (p = 1.40 × 10-6). Three heterozygous PTVs (p.Lys62∗, p.Tyr128Thrfs∗55, and p.Trp469∗, all absent from the gnomAD database) and an additional heterozygous missense mutation (p.Thr201Ser) were found in four KS probands. Notably, NDNF is expressed along the GnRH neuron migratory route in both mouse embryos and human fetuses and enhances GnRH neuron migration. Further, knock down of the zebrafish ortholog of NDNF resulted in altered GnRH migration. Finally, mice lacking Ndnf showed delayed GnRH neuron migration and altered olfactory axonal projections to the olfactory bulb; both results are consistent with a role of NDNF in GnRH neuron development. Altogether, our results highlight NDNF as a gene involved in the GnRH neuron migration implicated in KS.

中文翻译：

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神经元衍生的神经营养因子在先天性促性腺激素性性腺功能减退症中突变。

先天性性腺功能减退性腺功能减退症（CHH）是一种罕见的遗传性疾病，其特征在于不育和青春期缺乏。GnRH神经元迁移缺陷或GnRH分泌和/或作用改变会导致严重的促性腺激素释放激素（GnRH）缺乏。鉴于GnRH神经元与嗅觉原代轴突的密切发育联系，CHH通常与失眠或低渗有关，在这种情况下，其被定义为Kallmann综合征（KS）。CHH的遗传学是异质的，单独或组合涉及> 40个基因。几个控制GnRH个体发育的CHH相关基因编码包含纤连蛋白3（FN3）域的蛋白质，这对大脑和神经发育很重要。因此，我们假设其他FN3超家族基因的缺陷将成为CHH的基础。对240个CHH不相关的先证者进行了下一代测序，并针对FN3超家族基因中的稀有蛋白截短变体（PTV）进行了过滤。与gnomAD对照相比，CHH人群在神经元衍生的神经营养因子（NDNF）中的PTV统计学上富集（p = 1.40×10-6）。在四个KS先证者中发现了三个杂合PTV（p.Lys62 *，p.Tyr128Thrfs * 55和p.Trp469 *，均不存在于gnomAD数据库中）和一个额外的杂合错义突变（p.Thr201Ser）。值得注意的是，NDNF在小鼠胚胎和人类胎儿中均沿GnRH神经元迁移路径表达，并增强GnRH神经元迁移。此外，敲除NDNF的斑马鱼直系同源物导致改变的GnRH迁移。最后，缺乏Ndnf的小鼠表现出延迟的GnRH神经元迁移，并改变了嗅球轴突向嗅球的投射。这两个结果与NDNF在GnRH神经元发育中的作用一致。总而言之，我们的结果突出了NDNF作为参与KS的GnRH神经元迁移的基因。