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,由促性腺激素释放激素(GnRH)缺乏引起的遗传异质性生殖障碍。大约一半的CHH患者也有嗅觉下降或缺失,即Kallmann综合征(KS)。我们描述了由于POGZ中的杂合从头突变而患有White-Sutton综合征(发育迟缓和自闭症谱系障碍)和KS的患者(c.2857C>T,p.(Gln953*)),一种编码由锌指结构域衍生的pogo转座因子的基因,充当神经元网络的转录组调节剂。
方法:我们通过使用CRISPR/Cas9产生两个克隆人类多能干细胞系,模拟了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;编码截短的POGZ蛋白的p.E935Kfs*7;F6del系)。
结果:在分化为GnRH神经元的过程中,来自F6del系的神经祖细胞表现出严重的增殖缺陷,延迟伤口愈合能力,与WT和H11系相比,中间祖细胞神经元基因TBR1和TBR2以及未成熟神经元标记PAX6和TUBB3的下调,并产生更少的神经元,具有更短的神经突和更少的神经突分支点(P<0.005)。两条线,然而,可以成功分化为GnRH神经元。
结论:结论:这是关于White-Sutton综合征和CHH重叠的第一份报告.POGZ突变不会阻碍GnRH神经元的形成,但可能通过影响前神经祖细胞池的大小和运动性而导致CHH/KS,和神经突生长。
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.
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.