Skinningsrud Beate, Husebye Eystein S, Gilfillan Gregor D, Frengen Eirik, Erichsen Aage, Gervin Kristina, Ormerod Eli, Egeland Thore, Undlien Dag E
Department of Medical Genetics, Oslo University Hospital, Ullevål, N-0407 Oslo, Norway.
J Clin Endocrinol Metab. 2009 Oct;94(10):4086-93. doi: 10.1210/jc.2009-0923. Epub 2009 Sep 22.
X-linked congenital adrenal hypoplasia with hypogonadotropic hypogonadism (AHCH) is known to be caused by coding mutations in the nuclear receptor subfamily 0, group B, member 1 (NR0B1) gene, encoding the transcriptional repressor dosage-sensitive sex-reversal adrenal hypoplasia critical region on the X chromosome protein 1 (DAX1).
OBJECTIVE/PATIENTS: Four males in a family were affected by AHCH. Our aim was to locate the genetic cause of their disease, knowing that they had no mutation in the obvious candidate gene, NR0B1.
Linkage analysis of the X chromosome and mutational screening of conserved noncoding regions upstream of NR0B1 were performed. To functionally characterize the genetic defect, studies of transcription and expression of DAX1 and steroidogenic factor 1 (SF-1) were done.
A 60 Mb inversion on the X chromosome with one of the inversion breakpoints located in a conserved noncoding region 4 kb upstream of NR0B1 was detected. The inversion causes relocation of a putative SF-1 binding site implicated in murine gonadal development. A reporter construct lacking this enhancer element upstream of NR0B1 was unresponsive to SF-1 transcriptional activation. Immunohistochemistry suggested that the inversion leads to SF-1 silencing in the patients' testes both in childhood and in adult life.
We report a noncoding mutation causing AHCH, an inversion resulting in a phenotype similar to what is caused by intragenic NR0B1 null mutations. The inversion seems to disrupt and/or relocate regulatory sites crucial in DAX1 expression.
已知X连锁先天性肾上腺发育不全合并低促性腺激素性性腺功能减退(AHCH)是由核受体亚家族0、B组成员1(NR0B1)基因的编码突变引起的,该基因编码转录抑制因子X染色体上剂量敏感型性反转肾上腺发育不全关键区域蛋白1(DAX1)。
目的/患者:一个家族中的四名男性患有AHCH。我们的目的是找出他们患病的遗传原因,已知他们在明显的候选基因NR0B1中没有突变。
对X染色体进行连锁分析,并对NR0B1上游的保守非编码区进行突变筛查。为了从功能上表征遗传缺陷,对DAX1和类固醇生成因子1(SF-1)的转录和表达进行了研究。
检测到X染色体上一个60 Mb的倒位,其中一个倒位断点位于NR0B1上游4 kb的保守非编码区。该倒位导致一个与小鼠性腺发育有关的假定SF-1结合位点重新定位。在NR0B1上游缺少该增强子元件的报告基因构建体对SF-1转录激活无反应。免疫组织化学表明,该倒位导致患者童年和成年期睾丸中的SF-1沉默。
我们报告了一种导致AHCH的非编码突变,即一种倒位,其导致的表型与NR0B1基因内无效突变所导致的表型相似。该倒位似乎破坏和/或重新定位了对DAX1表达至关重要的调控位点。