Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
Receptor Biology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Genet Med. 2020 Aug;22(8):1329-1337. doi: 10.1038/s41436-020-0803-8. Epub 2020 Apr 28.
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 cosegregated 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 three 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.
促性腺激素释放激素（GnRH）神经元功能障碍可导致表型谱从青春期延迟到孤立性促性腺激素低下性性腺功能减退症（IHH）。我们试图确定这些病症的新遗传病因。
对一个常染色体显性遗传、明显青春期延迟的大家庭进行外显子组测序。在 GnRH 神经元细胞系中研究了该变体的作用。在患有 IHH 的大样本人群中寻找相同基因的变体。
我们在 DLG2 中发现了一种罕见的错义变体（F900V），该变体编码 PSD-93，与青春期延迟共分离。该变体在体外降低了 GnRH 的表达。PSD-93 是 NMDA 受体的锚定蛋白，NMDA 受体是一种谷氨酸受体，已被证实参与了实验室动物的青春期控制。F900V 变体损害了 PSD-93 与已知结合伴侣 Fyn 之间的相互作用，Fyn 可使 NMDA 受体磷酸化。在三个不相关的 IHH 家族中也发现了导致 GnRH 表达降低的 DLG2 变体。
这些发现表明 DLG2/PSD-93 中的变体导致常染色体显性遗传的青春期延迟，并且也可能导致 IHH。这些发现还表明，发病机制涉及 NMDA 受体信号转导受损，从而导致 GnRH 分泌减少。
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