Department of Endocrinology, Metabolism and Genetics, Henan Children's Hospital (aka. Children's Hospital Affiliated to Zhengzhou University), No-33, Longhu Waihuan East Road, Zhengzhou, 450018, China.
Department of Endocrinology, Metabolism and Genetics, Henan Children's Hospital (aka. Children's Hospital Affiliated to Zhengzhou University), No-33, Longhu Waihuan East Road, Zhengzhou, 450018, China.
Eur J Med Genet. 2021 May;64(5):104192. doi: 10.1016/j.ejmg.2021.104192. Epub 2021 Mar 23.
The case study unveils the likely mechanism of a novel stop-loss DAX1 variant preceding the prolonged precocious puberty in the adrenal hypoplasia congenital (AHC) boy. A boy aged five years and nine months initially examined for the primary adrenal insufficiency symptoms. Next-generation sequencing confirmed the X-linked inheritance of a novel stop-loss DAX1 variant: c.1411T>C/p.Ter471Gln associated with AHC in the patient. The patient was subjected to a brief clinical follow-up from 11 to 15.1 years of age. The effect of the mutant-DAX1 variant (p.Ter471Gln) on DAX1-steroidogenic factor 1 (SF1) (protein-protein) interaction was studied by protein-protein docking using the ClusPro-online tool. At 5.9 yrs of age, the patient exhibited precocious puberty with the secondary sexual characteristics of Tanner 2 stage (of 9-14 yrs of age). The patient showed primary adrenal insufficiency with diminished cortisol concentrations at blood serum (25 ng/ml) and urine (3.55 μg/24 h) levels. Upon steroidal exposure, the patient showed normalized serum cortisol levels of 45-61 ng/ml. However, the precocious puberty got prolonged with the increased penis length of 8.5 cm and the bone age of 18 yrs old during the follow-up. The patient showed increased basal serum adrenocorticotropic hormone (110->2000 pg/ml) and follicle-stimulating hormone (18.4-22.3 mIU/ml) concentrations. Following an elevated hypothalamic-pituitary-gonadal axis activity witnessed upon gonarellin stimulation. Protein-protein docking confirmed a weaker interaction between the mutant-DAX1 (p.Ter471Gln) protein and the wild-SF1 protein. Overall, we hypothesize the weakened mutant-DAX1-SF1 (protein-protein) interaction could govern the prolonged precocious puberty augmented with the elevated hypothalamic-pituitary-gonadal/adrenal axis responses via SF1-induced neuronal nitric oxide synthetase activation in the patient.
该病例研究揭示了一种新型的 DAX1 终止变异，该变异可能导致肾上腺发育不全先天性（AHC）男孩的早熟提前发生。一个五岁九个月大的男孩最初因原发性肾上腺功能不全的症状而接受检查。下一代测序证实了一种新型的 DAX1 终止变异的 X 连锁遗传：c.1411T>C/p.Ter471Gln 与患者的 AHC 相关。对患者进行了从 11 岁到 15.1 岁的简短临床随访。使用 ClusPro-online 工具进行蛋白质-蛋白质对接，研究了突变型 DAX1 变体（p.Ter471Gln）对 DAX1-类固醇生成因子 1（SF1）（蛋白-蛋白）相互作用的影响。在 5.9 岁时，患者出现了性早熟，第二性征为 Tanner 2 期（9-14 岁）。患者表现为原发性肾上腺功能不全，血清（25ng/ml）和尿液（3.55μg/24h）皮质醇浓度降低。在类固醇暴露后，患者的血清皮质醇水平正常，为 45-61ng/ml。然而，性早熟持续延长，阴茎长度增加了 8.5cm，骨龄为 18 岁。患者的基础血清促肾上腺皮质激素（110->2000pg/ml）和卵泡刺激素（18.4-22.3mIU/ml）浓度升高。在促性腺激素释放素刺激下观察到下丘脑-垂体-性腺轴活性升高。蛋白质-蛋白质对接证实，突变型 DAX1（p.Ter471Gln）蛋白与野生型 SF1 蛋白之间的相互作用较弱。总的来说，我们假设，突变型 DAX1-SF1（蛋白-蛋白）相互作用减弱可能通过 SF1 诱导的神经元一氧化氮合酶激活来控制延长的性早熟，从而增强下丘脑-垂体-性腺/肾上腺轴的反应，导致患者出现性早熟。
