Hypogonadotropic hypogonadism in subjects with DAX1 mutations.
Hypogonadotropic hypogonadism in subjects with DAX1 mutations.
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DOI：
10.1016/j.mce.2011.04.017
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发表时间：
2011-10-22
影响因子：
4.1
通讯作者：
Jameson, J. Larry
中科院分区：
文献类型：
--
作者：
Jadhav, Unmesh;Harris, Rebecca M.;Jameson, J. Larry
DAX1(剂量敏感性反转，肾上腺发育不良临界区，位于X染色体上，基因1；也称为NROB1，核受体亚家族0，B组，成员1)编码一种核受体，表达于胚胎干细胞、类固醇生成组织(性腺、肾上腺)、下丘脑腹内侧部(VMH)和垂体促性腺激素。携带DAX1基因突变的人类会患上X连锁综合征，称为先天性肾上腺发育不良(AHC)。这些男孩通常在婴儿时期患有肾上腺功能衰竭，但后来由于性腺激素低减(HHG)而无法经历青春期。肾上腺功能衰竭反映了胎儿向成人区过渡过程中的发育异常，导致糖皮质激素和盐皮质激素缺乏。HHG的病因涉及下丘脑GnRH分泌和/或垂体对GnRH反应的综合和可变缺陷，导致低促黄体生成素、卵泡刺激素和睾酮。外源性促性腺激素治疗一般不会诱导精子发生。动物模型表明，DAX1在睾丸发育和功能中也起着关键作用。作为一种核受体，DAX1被证明是一种转录抑制因子，特别是受其他核受体调节的途径，如类固醇生成因子1(SF1)。除了生殖组织外，DAX1在ES细胞中也高水平表达，并在维持多能性方面发挥作用。在这里，我们回顾了与DAX1突变相关的临床表现以及基于动物模型和体外研究的关于DAX1功能的不断发展的信息。
DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1; also known as NROB1, nuclear receptor subfamily 0, group B, member 1) encodes a nuclear receptor that is expressed in embryonic stem (ES) cells, steroidogenic tissues (gonads, adrenals), the ventromedial hypothalamus (VMH), and pituitary gonadotropes. Humans with DAX1 mutations develop an X-linked syndrome referred to as adrenal hypoplasia congenita (AHC). These boys typically present in infancy with adrenal failure but later fail to undergo puberty because of hypogonadotropic hypogonadism (HHG). The adrenal failure reflects a developmental abnormality in the transition of the fetal to adult zone, resulting in glucocorticoid and mineralocorticoid deficiency. The etiology of HHG involves a combined and variable deficiency of hypothalamic GnRH secretion and/or pituitary responsiveness to GnRH resulting in low LH, FSH and testosterone. Treatment with exogenous gonadotropins generally does not induce spermatogenesis. Animal models indicate that DAX1 also plays a critical role in testis development and function. As a nuclear receptor, DAX1 has been shown to function as a transcriptional repressor, particularly of pathways regulated by other nuclear receptors, such as steroidogenic factor 1 (SF1). In addition to reproductive tissues, DAX1 is also expressed at high levels in ES cells and plays a role in the maintenance of pluripotentiality. Here we review the clinical manifestations associated with DAX1 mutations as well as the evolving information about its function based on animal models and in vitro studies.
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影响因子：
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