Correa Rafaela V, Domenice Sorahia, Bingham Nathan C, Billerbeck Ana Elisa C, Rainey William E, Parker Keith L, Mendonca Berenice B
Developmental Endocrinology Unit, Hospital das Clínicas, Faculdade Medicina Universidade de São Paulo, São Paulo 05403-900, Brazil.
J Clin Endocrinol Metab. 2004 Apr;89(4):1767-72. doi: 10.1210/jc.2003-031240.
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.
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的基因敲除小鼠会出现肾上腺和性腺发育不全、促性腺激素表达受损以及腹内侧下丘脑核结构异常。先前的研究已鉴定出三名SF-1发生突变的人类受试者，这些突变导致肾上腺皮质功能不全并伴有不同程度的性腺功能障碍。我们现在描述了一种新的SF-1 8碱基对微缺失，它是从一名46，XY患者中分离出来的，该患者表现为性腺发育不全但肾上腺功能正常，这种微缺失导致在编码激活功能2结构域的序列上游出现过早终止。在细胞转染实验中，突变蛋白不具有内在转录活性，反而在大多数细胞类型中抑制野生型蛋白的功能。据我们所知，这是人类中SF-1突变产生明显显性负效应的首个例子。这些发现定义了一种SF-1突变，该突变显然在体内对肾上腺皮质和性腺的转录活性有不同影响，可能与出现46，XY性反转但肾上腺功能正常的患者群体有关。
