Analysis of DAX1 (NR0B1) and steroidogenic factor-1 (NR5A1) in children and adults with primary adrenal failure: ten years' experience.
Analysis of DAX1 (NR0B1) and steroidogenic factor-1 (NR5A1) in children and adults with primary adrenal failure: ten years' experience.
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DOI：
10.1210/jc.2006-0603
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发表时间：
2006-08
期刊：
影响因子：
--
通讯作者：
Achermann JC
中科院分区：
文献类型：
--
作者：
Lin L;Gu WX;Ozisik G;To WS;Owen CJ;Jameson JL;Achermann JC
原发性肾上腺功能衰竭是一种危及生命的疾病，可由一系列原因引起，包括自身免疫、代谢和发育障碍。核受体DAX1(NR0B1)和类固醇生成因子-1(SF1/Ad4BP，NR5A1)在肾上腺发育和功能中起重要作用，在肾上腺发育不全患者中发现了这些转录因子的突变。目的探讨原因不明(非先天性肾上腺增生症、肾上腺脑白质营养不良、自身免疫性疾病)的儿童和成人肾上腺功能衰竭患者中DAX1和SF1基因突变的发生率。共纳入117例患者。88例患儿为婴儿期或儿童期肾上腺发育不全或原发原因不明的肾上腺功能衰竭患者(，46，XY表型男性；17，46，XY性腺发育不全/雄激素生成受损；7，46，XX女性)。29名成年后出现病因不明的“爱迪生病”患者。直接测序分析DAX1(NR0B1)(包括外显子2α/1A)和SF1(NR5A1)的突变在伴有肾上腺发育不良的46，XY表型男童中，DAX1基因突变的发生率为58%(37/)，所有伴有性腺激素减退和男性肾上腺功能衰竭家族史的男童中均有DAX1基因突变。仅在2例46，XY性腺发育不全患者中发现导致肾上腺功能衰竭的SF1突变。在成人起病组中未发现DAX1或SF1突变。在这组男孩中，DAX1突变是导致肾上腺功能衰竭的相对常见的原因。在人类中，导致肾上腺功能衰竭的SF1突变是罕见的，在46，XY个体中更有可能与显著的雄激素不足和性腺功能障碍有关。
Primary adrenal failure is a life-threatening condition that can be caused by a range of etiologies, including autoimmune, metabolic, and developmental disorders. The nuclear receptors DAX1 (NR0B1) and steroidogenic factor-1 (SF1/Ad4BP, NR5A1) play an important role in adrenal development and function, and mutations in these transcription factors have been found in patients with adrenal hypoplasia. To investigate the prevalence of DAX1 and SF1 mutations in children and adults with primary adrenal failure of unknown etiology (i.e., not caused by congenital adrenal hyperplasia, adrenoleukodystrophy, autoimmune disease). One-hundred and seventeen patients were included. Eighty-eight individuals presented in infancy or childhood with adrenal hypoplasia or primary adrenal failure of unknown etiology (n=64, 46,XY phenotypic males; n=17, 46,XY gonadal dysgenesis/impaired androgenization; n=7, 46,XX females). Twenty-nine individuals presented in adulthood with “Addison disease” of unknown etiology. Mutational analysis of DAX1 (NR0B1) (including exon 2α/1A) and SF1 (NR5A1) by direct sequencing. DAX1 mutations were found in 58% (37/64) of 46,XY phenotypic boys referred with adrenal hypoplasia, and in all boys (8/8) with hypogonadotropic hypogonadism and a family history suggestive of adrenal failure in males. SF1 mutations causing adrenal failure were found only in two patients with 46,XY gonadal dysgenesis. No DAX1 or SF1 mutations were identified in the adult-onset group. DAX1 mutations are a relatively frequent cause of adrenal failure in this group of boys. SF1 mutations causing adrenal failure in humans are rare and are more likely to be associated with significant underandrogenization and gonadal dysfunction in 46,XY individuals.
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