A microdeletion in the ligand binding domain of human steroidogenic factor 1 causes XY sex reversal without adrenal insufficiency
A microdeletion in the ligand binding domain of human steroidogenic factor 1 causes XY sex reversal without adrenal insufficiency
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DOI：
10.1210/jc.2003-031240
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发表时间：
2004-04-01
影响因子：
5.8
通讯作者：
Mendonca, BB
中科院分区：
文献类型：
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作者：
Correa, RV;Domenice, S;Mendonca, BB
类固醇生成因子1（SF-1）是一种孤儿核受体，在内分泌发育和功能中起关键作用。缺乏SF-1基因敲除小鼠具有肾上腺和性腺发育不全、促性腺激素表达受损和下丘脑腹内侧核结构异常。以前的研究已经确定了三个人类受试者与突变的SF-1导致肾上腺皮质功能不全，不同程度的性腺功能障碍。我们现在描述一种新的8-bp的SF-1的微缺失，从一个46，XY患者谁提出了性腺发育不全，但正常的肾上腺功能，这会导致提前终止上游的序列编码的激活功能2域。在细胞转染实验中，突变的蛋白质不具有内在的转录活性，而是在大多数细胞类型中抑制野生型蛋白质的功能。据我们所知，这是SF-1突变在人类中明显显性负效应的第一个例子。这些发现，定义了SF-1突变，明显差异影响其在肾上腺皮质和性腺中的体内转录活性，可能与46，XY性逆转但肾上腺功能正常的患者队列相关。
Steroidogenic factor 1 (SF-1) is an orphan nuclear receptor that plays key roles in endocrine development and function. Knockout mice lacking SF-1 have adrenal and gonadal agenesis, impaired gonadotropin expression, and structural abnormalities of the ventromedial hypothalamic nucleus. Previous studies have identified three human subjects with mutations in SF-1 causing adrenocortical insufficiency with varying degrees of gonadal dysfunction. We now describe a novel 8-bp microdeletion of SF-1, isolated from a 46, XY patient who presented with gonadal agenesis but normal adrenal function, which causes premature termination upstream of sequences encoding the activation function 2 domain. In cell transfection experiments, the mutated protein possessed no intrinsic transcriptional activity but rather inhibited the function of the wild-type protein in most cell types. To our knowledge, this is the first example of an apparent dominant-negative effect of a SF-1 mutation in humans. These findings, which define a SF-1 mutation that apparently differentially affects its transcriptional activity in vivo in the adrenal cortex and the gonads, may be relevant to the cohort of patients who present with 46, XY sex reversal but normal adrenal function.