Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, 20892, USA; Endocrine and Diabetes Unit. Edmond and Lily Safra Children's Hospital, Tel-Hashomer. Ramat Gan. Sackler School of Medicine, Ramat-aviv, Israel.
Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, 20892, USA.
Mol Cell Endocrinol. 2021 Jan 15;520:111071. doi: 10.1016/j.mce.2020.111071. Epub 2020 Oct 27.
Phosphodiesterases catalyze the hydrolysis of cyclic nucleotides and maintain physiologic levels of intracellular concentrations of cyclic adenosine and guanosine mono-phosphate (cAMP and cGMP, respectively). Increased cAMP signaling has been associated with adrenocortical tumors and Cushing syndrome. Genetic defects in phosphodiesterase 11A (PDE11A) may lead to increased cAMP signaling and have been found to predispose to the development of adrenocortical, prostate, and testicular tumors. A previously reported Pde11a knockout (Pde11a) mouse line was studied and found to express PDE11A mRNA and protein still, albeit at reduced levels; functional studies in various tissues showed increased cAMP levels and reduced PDE11A activity. Since patients with PDE11A defects and Cushing syndrome have PDE11A haploinsufficiency, it was particularly pertinent to study this hypomorphic mouse line. Indeed, Pde11a mice failed to suppress corticosterone secretion in response to low dose dexamethasone, and in addition exhibited adrenal subcapsular hyperplasia with predominant fetal-like features in the inner adrenal cortex, mimicking other mouse models of increased cAMP signaling in the adrenal cortex. We conclude that a previously reported Pde11a mouse showed continuing expression and function of PDE11A in most tissues. Nevertheless, Pde11a partial inactivation in mice led to an adrenocortical phenotype that was consistent with what we see in patients with PDE11A haploinsufficiency.
磷酸二酯酶催化环核苷酸的水解，维持细胞内环腺苷酸和鸟苷酸单磷酸（分别为 cAMP 和 cGMP）的生理浓度。cAMP 信号的增加与肾上腺皮质肿瘤和库欣综合征有关。磷酸二酯酶 11A（PDE11A）的遗传缺陷可能导致 cAMP 信号的增加，并被发现易患肾上腺皮质、前列腺和睾丸肿瘤。先前报道的 Pde11a 敲除（Pde11a）小鼠系进行了研究，发现尽管水平降低，但仍表达 PDE11A mRNA 和蛋白；在各种组织中的功能研究表明 cAMP 水平增加和 PDE11A 活性降低。由于 PDE11A 缺陷和库欣综合征患者存在 PDE11A 杂合不足，因此特别需要研究这种低功能小鼠系。事实上，Pde11a 小鼠未能对低剂量地塞米松抑制皮质酮的分泌，此外还表现出肾上腺皮质下增生，内肾上腺皮质以类似于其他增加 cAMP 信号的小鼠模型的胎儿样特征为主，模拟其他增加 cAMP 信号的小鼠模型在肾上腺皮质中的表现。我们得出结论，先前报道的 Pde11a 小鼠在大多数组织中仍然表现出 PDE11A 的持续表达和功能。然而，Pde11a 在小鼠中的部分失活导致了与我们在 PDE11A 杂合不足患者中看到的一致的肾上腺皮质表型。
