Knockout mice for the kisspeptin receptor, Kiss1r (Kiss1r^−/−) and its ligand kisspeptin, Kiss1 (Kiss1^−/−) replicate the phenotype of isolated hypogonadotropic hypogonadism (IHH) associated with variants of these genes in humans. A recent report suggests that kisspeptin may be involved in human fetal adrenocortical development and function. Herein, we characterized the adrenal function and morphology in Kiss1^−/− mice that do not go through normal puberty. Two fetal markers were expressed in eosinophilic cells potentially derived from the X-zone that should disappear at puberty in male mice and during the first pregnancy in female animals. Although the hypercorticosteronism observed in Kiss1^−/− females corrected overtime, hyperaldosteronism persisted at 14 months and correlated with the overexpression of Star. To determine if KISS1 and KISS1R genes are involved in the development of primary aldosteronism (PA) and hypercortisolism [Cushing’s syndrome (CS)] in humans, we sequenced these 2 genes in 65 patients with PA and/or CS. Interestingly, a patient with CS presented with a germline KISS1 variant (p.H90D, rs201073751). We also found three rare variants in the KISS1R gene in three patients with PA: p.C95W (rs141767649), p.A189T (rs73507527) and p.R229R (rs115335009). The two missense variants have been previously associated with IHH. Our findings suggest that KISS1 may play a role in adrenal function in mice and possibly adrenocortical steroid hormone secretion in humans, beyond its recently described role in human fetal adrenocortical development.

中文翻译：

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Kisspeptin 缺乏会导致肾上腺异常和类固醇激素分泌过多


Kisspeptin 受体Kiss1r ( Kiss1r ^−/− ) 及其配体 Kisspeptin Kiss1 ( Kiss1 ^−/− ) 的基因敲除小鼠复制了与人类这些基因变体相关的孤立的低促性腺素性性腺功能减退症 (IHH) 表型。最近的一份报告表明 Kisspeptin 可能参与人类胎儿肾上腺皮质的发育和功能。在此，我们表征了未经历正常青春期的Kiss1 ^−/−小鼠的肾上腺功能和形态。两种胎儿标志物在可能源自 X 区的嗜酸性细胞中表达，这些细胞在雄性小鼠的青春期和雌性动物的第一次怀孕期间应该消失。尽管在Kiss1 ^−/−雌性小鼠中观察到的皮质酮增多症随着时间的推移得到了纠正，但醛固酮增多症持续到 14 个月，并且与Star的过度表达相关。为了确定KISS1和KISS1R基因是否参与人类原发性醛固酮增多症 (PA) 和皮质醇增多症 [库欣综合征 (CS)] 的发展，我们对 65 名 PA 和/或 CS 患者的这 2 个基因进行了测序。有趣的是，一名 CS 患者出现种系KISS1变异（p.H90D，rs201073751）。我们还在三名 PA 患者的KISS1R基因中发现了三种罕见变异：p.C95W (rs141767649)、p.A189T (rs73507527) 和 p.R229R (rs115335009)。这两个错义变体之前已被认为与 IHH 有关。 我们的研究结果表明， KISS1可能在小鼠肾上腺功能中发挥作用，并且可能在人类肾上腺皮质类固醇激素分泌中发挥作用，超出了最近描述的在人类胎儿肾上腺皮质发育中的作用。