Two Novel Mutations in Splice Donor Sites of CYP11B1 in Congenital Adrenal Hyperplasia Due to 11β-Hydroxylase Deficiency
Two Novel Mutations in Splice Donor Sites of CYP11B1 in Congenital Adrenal Hyperplasia Due to 11β-Hydroxylase Deficiency
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DOI：
10.3109/07435800009048602
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发表时间：
2000-01
影响因子：
2.1
通讯作者：
O. Chabre;S. Portrat-Doyen;J. Vivier;Y. Morel;G. Defaye
中科院分区：
文献类型：
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作者：
O. Chabre;S. Portrat-Doyen;J. Vivier;Y. Morel;G. Defaye
我们提出了一个体内和体外研究先天性肾上腺增生的患者11β-羟化酶缺乏症。遗传分析显示CYP11B1有两个新的碱基替换，一个是外显子5最后一个碱基的保守过渡，另一个是内含子8的IVS8+4AG过渡。抑制治疗的困难导致了严重的高血压。腹腔镜肾上腺切除术后血压恢复正常。在体外，肾上腺细胞的类固醇生成未显示可测量的11β-羟化酶活性。通过RT-PCR和测序对CYP11B1 mRNA进行分析，发现表达了一个缺少8号外显子的mRNA，可能是由8号内含子突变引起的。此外，检测到1、2、8、9外显子对应的mRNA高度截断，3-7外显子缺失，可能与外显子5突变有关。Western blot分析显示CYP11B免疫反应带较短，为43 kDa，与第8外显子的截断一致。因此，该患者的肾上腺切除术可以有效治疗严重高血压，并有助于了解导致CYP11B1异常剪接的两种新突变的机制
We present an in vivo and in vitro study of congenital adrenal hyperplasia in a patient with 11β-hydroxylase deficiency. Genetic analysis showed two new base substitutions of CYP11B1, a conservative transition at the last base of exon 5, and a IVS8+4AG transition in intron 8. Difficulties with suppressive therapy resulted in severe hypertension. A laparoscopic adrenalectomy was decided which lead to normalization of blood pressure. In vitro, steroidogenesis by adrenal cells showed no measurable 11β-hydroxylase activity. Analysis of CYP11B1 mRNA by RT-PCR and sequencing showed expression of a mRNA which lacked exon 8, presumably resulting from the intron 8 mutation. In addition a highly truncated mRNA was detected corresponding to exons 1, 2, 8, 9, with the loss of exons 3–7, presumably related to the exon 5 mutation. Western blot analysis showed a shorter CYP11B immunoreactive band of 43 kDa, consistent with truncation of exon 8. Thus adrenalectomy in this patient allowed effective treatment of severe hypertension and helped to understand the mechanisms of two novel mutations responsible for aberrant splicing of CYP11B1