OBJECTIVE Congenital hypogonadotropic hypogonadism (CHH) is a rare, genetically heterogeneous reproductive disorder caused by gonadotropin-releasing hormone (GnRH) deficiency. Approximately half of CHH patients also have decreased or absent sense of smell, that is, Kallmann syndrome (KS). We describe a patient with White-Sutton syndrome (developmental delay and autism spectrum disorder) and KS due to a heterozygous de novo mutation in POGZ (c.2857C>T, p.(Gln953*)), a gene encoding pogo transposable element derived with zinc finger domain, which acts as a transcriptomic regulator of neuronal networks. DESIGN AND METHODS We modeled the role of POGZ in CHH by generating 2 clonal human pluripotent stem cell lines with CRISPR/Cas9, carrying either the heterozygous patient mutation (H11 line) or a homozygous mutation (c.2803-2906del; p.E935Kfs*7 encoding a truncated POGZ protein; F6del line). RESULTS During the differentiation to GnRH neurons, neural progenitors derived from F6del line displayed severe proliferation defect, delayed wound-healing capacity, downregulation of intermediate progenitor neuron genes TBR1 and TBR2, and immature neuron markers PAX6 and TUBB3 and gave rise to fewer neurons with shorter neurites and less neurite branch points compared to the WT and H11 lines (P < .005). Both lines, however, could be successfully differentiated to GnRH neurons. CONCLUSIONS In conclusion, this is the first report on the overlap between White-Sutton syndrome and CHH. POGZ mutations do not hinder GnRH neuron formation but may cause CHH/KS by affecting the size and motility of the anterior neural progenitor pool and neurite outgrowth.

中文翻译：

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患有新发 POGZ 突变的先天性低促性腺激素性性腺功能减退症。

目的 先天性低促性腺激素性性腺功能减退症 (CHH) 是一种罕见的遗传异质性生殖疾病，由促性腺激素释放激素 (GnRH) 缺乏引起。大约一半的 CHH 患者还伴有嗅觉减退或缺失，即卡尔曼综合征 (KS)。我们描述了一名因 POGZ (c.2857C>T, p.(Gln953*)) 杂合性从头突变而患有 White-Sutton 综合征（发育迟缓和自闭症谱系障碍）和 KS 的患者，POGZ 是一种编码 pogo 转座元件的基因具有锌指结构域，充当神经元网络的转录组调节因子。设计和方法我们通过使用 CRISPR/Cas9 生成 2 个克隆人多能干细胞系来模拟 POGZ 在 CHH 中的作用，这些细胞系携带杂合患者突变（H11 系）或纯合突变（c.2803-2906del；p.E935Kfs* 7 编码截短的 POGZ 蛋白；F6del 系）。结果 在向 GnRH 神经元分化过程中，F6del 系衍生的神经祖细胞表现出严重的增殖缺陷、伤口愈合能力延迟、中间祖神经元基因 TBR1 和 TBR2 以及不成熟神经元标记 PAX6 和 TUBB3 的下调，并且产生的神经元数量较少，长度较短。与 WT 和 H11 系相比，轴突和轴突分支点更少 (P < .005)。然而，这两个细胞系都可以成功分化为 GnRH 神经元。结论 总之，这是关于 White-Sutton 综合征和 CHH 之间重叠的第一份报告。POGZ 突变不会阻碍 GnRH 神经元形成，但可能通过影响前神经祖细胞池的大小和运动性以及神经突生长而导致 CHH/KS。