Identification of a novel missense mutation that is as damaging to DAX-1 repressor function as a nonsense mutation
Identification of a novel missense mutation that is as damaging to DAX-1 repressor function as a nonsense mutation
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DOI：
10.1210/jc.2002-021560
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发表时间：
2003-03-01
影响因子：
5.8
通讯作者：
Anderson, RA
中科院分区：
文献类型：
--
作者：
Brown, P;Scobie, GA;Anderson, RA
DAX-1（NROB1）基因突变导致X连锁先天性肾上腺发育不全（AHC）和低促性腺激素性性腺功能减退症。其临床表现通常为早期肾上腺功能不全，在预期青春期时检测到低促性腺激素性性腺功能减退。在这项研究中，我们确定了两名AHC患者DAX-1基因的突变。一个突变，Y399X，导致提前终止密码子，并与人绒毛膜促性腺激素的Leydig细胞反应性的损失。第二个，L297 P，是一个错义突变，人绒毛膜促性腺激素的反应性得以维持。亲属关系分析确定这些突变是从先证者的母亲那里遗传的。L297 P以前没有描述过，并且存在于高度保守的结合基序（LLXLXL）内。瞬时转染试验表明，这两种突变导致DAX-1阻遏物活性的严重损失。从患有Y399X突变的受试者的受影响兄弟姐妹中获得的睾丸组织的免疫组织化学分析显示正常的睾丸形态和DAX-1，类固醇生成因子-1和抗苗勒管激素蛋白的表达。这些数据扩展了DAX-1突变的临床和分子信息，证实了新生儿阶段的正常睾丸发育，并说明了Leydig细胞功能的变异性。
Mutations in the DAX-1 (NROB1) gene result in X-linked congenital adrenal hypoplasia (AHC) and hypogonadotropic hypogonadism. The clinical presentation is usually as adrenal insufficiency in early life, with hypogonadotropic hypogonadism detected at the time of expected puberty. In this study we identified mutations in the DAX-1 gene of two patients with AHC. One mutation, Y399X, resulted in a premature stop codon and was associated with loss of Leydig cell responsiveness to human chorionic gonadotropin. The second, L297P, was a missense mutation, and human chorionic gonadotropin responsiveness was maintained. Kindred analysis established that the mutations had been inherited from the proband's mothers. The L297P has not been described previously and occurs within a highly conserved binding motif (LLXLXL). Transient transfection assays demonstrated that both mutations resulted in a severe loss of DAX-1 repressor activity. Immunohistochemical analysis of testicular tissue obtained from an affected sibling of the subject with the Y399X mutation, who had died with adrenal failure as a neonate, showed normal testicular morphology and expression of DAX-1, steroidogenic factor-1, and anti-Mullerian hormone protein. These data extend the clinical and molecular information on DAX-1 mutations, confirm normal testicular development at the neonatal stage, and illustrate variability in Leydig cell function.