DLG2 variants in patients with pubertal disorders.
DLG2 variants in patients with pubertal disorders.
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DOI：
10.1038/s41436-020-0803-8
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发表时间：
2020-08
期刊：
影响因子：
--
通讯作者：
Baron J
中科院分区：
文献类型：
--
作者：
Jee YH;Won S;Lui JC;Jennings M;Whalen P;Yue S;Temnycky AG;Barnes KM;Cheetham T;Boden MG;Radovick S;Quinton R;Leschek EW;Aguilera G;Yanovski JA;Seminara SB;Crowley WF;Delaney A;Roche KW;Baron J
促性腺激素释放激素 (GnRH) 神经元功能受损可导致一系列表型，从青春期延迟到孤立性低促性腺激素性性腺功能减退症 (IHH)。我们试图找出这些病症的新遗传病因。外显子组测序是在一个常染色体显性遗传、青春期明显延迟的大家庭中进行的。在 GnRH 神经元细胞系中研究了该变体的影响。在一大群 IHH 患者中寻找同一基因的变异体。我们在DLG2（编码PSD-93）中发现了一个罕见的错义变异（F900V），它与青春期延迟共分离。该变体在体外降低了 GnRH 表达。 PSD-93 是 NMDA 受体的锚定蛋白，NMDA 受体是一种谷氨酸受体，与实验动物青春期的控制有关。 F900V 变体损害了 PSD-93 和已知的结合伙伴 Fyn 之间的相互作用，Fyn 会磷酸化 NMDA 受体。在 3 个不相关的 IHH 家族中发现了 DLG2 的变体，该变体也降低了 GnRH 的表达。研究结果表明，DLG2/PSD-93 的变异会导致常染色体显性青春期延迟，也可能导致 IHH。研究结果还表明，发病机制涉及 NMDA 受体信号传导受损，从而导致 GnRH 分泌减少。
Impaired function of gonadotropin-releasing hormone (GnRH) neurons can cause a phenotypic spectrum ranging from delayed puberty to isolated hypogonadotropic hypogonadism (IHH). We sought to identify a new genetic etiology for these conditions. Exome sequencing was performed in an extended family with autosomal dominant, markedly delayed puberty. The effects of the variant were studied in a GnRH neuronal cell line. Variants in the same gene were sought in a large cohort of individuals with IHH. We identified a rare missense variant (F900V) in DLG2 (which encodes PSD-93) that co-segregated with the delayed puberty. The variant decreased GnRH expression in vitro. PSD-93 is an anchoring protein of NMDA receptors, a type of glutamate receptor that has been implicated in the control of puberty in laboratory animals. The F900V variant impaired the interaction between PSD-93 and a known binding partner, Fyn, which phosphorylates NMDA receptors. Variants in DLG2 that also decreased GnRH expression were identified in 3 unrelated families with IHH. The findings indicate that variants in DLG2/PSD-93 cause autosomal dominant delayed puberty and may also contribute to IHH. The findings also suggest that the pathogenesis involves impaired NMDA receptor signaling and consequently decreased GnRH secretion.
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影响因子：
4.8
作者：
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通讯作者：
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DOI：
10.1073/pnas.0811025106
发表时间：
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作者：
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DOI：
10.1073/pnas.1517045112
发表时间：
2015-12-15
影响因子：
11.1
作者：
Chen, Xiaobing;Levy, Jonathan M.;Reese, Thomas S.
通讯作者：
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