Seven Novel DAX1 Mutations with Loss of Function Identified in Chinese Patients with Congenital Adrenal Hypoplasia
Seven Novel DAX1 Mutations with Loss of Function Identified in Chinese Patients with Congenital Adrenal Hypoplasia
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中国先天性肾上腺发育不全患者中发现七种新的 DAX1 功能丧失突变
DOI：
10.1210/jc.2009-2408
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发表时间：
2010-09-01
影响因子：
5.8
通讯作者：
Li, Xiaoying
中科院分区：
文献类型：
--
作者：
Li, Na;Liu, Ruya;Li, Xiaoying
背景：DAX1（剂量敏感型性逆转，X 染色体上的先天性肾上腺发育不全关键区域，基因 1；也称为 NROB1）突变通过 SF-1（类固醇生成因子 1）介导的 StAR（类固醇生成急性调节蛋白）和 LH β 反式抑制的丧失，导致先天性肾上腺发育不全 (AHC) 患者的肾上腺功能衰竭和促性腺功能减退症。转录活性和 GnRH 表达的减少。详细研究了 AHC 患者的临床特征与基因遗传和功能改变的相关性。 目的：本研究旨在鉴定中国 AHC 患者中的 DAX1 突变，并调查检测到的新突变的功能缺陷。 患者和方法：从 8 个家庭招募了 9 名 AHC 患者。对DAX1突变进行了筛选，并在体外评估了所识别突变的转录活性。结果：参与研究的所有9名患者均检测到DAX1突变，其中有8种不同的突变。其中，7 个为新突变，包括 2 个错义突变（L262P 和 C368F）、1 个无义突变（Q222X）和 4 个移码突变（637delC、652_653delAC、973delC 和 774_775insCC）。功能研究表明，突变体 DAX1 因核定位、StAR 和 LH β 转录活性反式抑制的丧失以及 GnRH 表达减少而受到损害。结论：这些发现提供了对 DAX1 突变影响下丘脑-垂体-性腺和下丘脑-垂体-肾上腺轴并导致 AHC 和低促性腺激素性腺功能减退症的分子事件的深入了解。 （临床内分泌代谢杂志 95：E104-E111，2010）
Context: DAX1 (for dosage-sensitive sex reversal, adrenal hypoplasia congenital critical region on the X chromosome, gene 1; also called NROB1) mutations are responsible for adrenal failure and hypogonadotropic hypogonadism in patients with adrenal hypoplasia congenita (AHC), through a loss of trans-repression of SF-1 (for steroidogenic factor-1)-mediated StAR (for steroidogenic acute regulatory protein) and LH beta transcriptional activities and a reduction of GnRH expression. The correlation of clinical features with genetic and functional alterations of the gene was investigated in detail in AHC patients.Objective: The present study aimed at identifying DAX1 mutations in Chinese AHC patients and investigating the functional defects of detected novel mutations.Patients and Methods: Nine patients with AHC were recruited from eight families. DAX1 mutations were screened, and the transcriptional activities of the identified mutations were assessed in vitro.Results: DAX1 mutations were detected in all nine patients enrolled in the study, with eight different mutations. Among the latter, seven are novel mutations, including two missense (L262P and C368F), one nonsense (Q222X), and four frame-shift (637delC, 652_653delAC, 973delC, and 774_775insCC) mutations. The functional studies showed that the mutant DAX1 was impaired by nuclear localization, loss of trans-repression of StAR and LH beta transcriptional activities, and reduction of GnRH expression.Conclusion: These findings provide insight into the molecular events by which DAX1 mutations influence the hypothalamus-pituitary-gonadal and hypothalamus-pituitary-adrenal axis and lead to AHC and hypogonadotropic hypogonadism. (J Clin Endocrinol Metab 95: E104-E111, 2010)