Polat Seher, Kulle Alexandra, Karaca Züleyha, Akkurt Ilker, Kurtoglu Selim, Kelestimur Fahrettin, Grötzinger Joachim, Holterhus Paul-Martin, Riepe Felix G
Department of Medical Genetics, Erciyes University, Kayseri, Turkey.
Eur J Endocrinol. 2014 Apr 10;170(5):697-706. doi: 10.1530/EJE-13-0737. Print 2014 May.
Congenital adrenal hyperplasia (CAH) is one of the most common autosomal recessive inherited endocrine diseases. Steroid 11β-hydroxylase (P450c11) deficiency (11OHD) is the second most common form of CAH.
The aim of the study was to study the functional consequences of three novel CYP11B1 gene mutations (p.His125Thrfs*8, p.Leu463_Leu464dup and p.Ser150Leu) detected in patients suffering from 11OHD and to correlate this data with the clinical phenotype.
Functional analyses were done by using a HEK293 cell in vitro expression system comparing WT with mutant P450c11 activity. Mutant proteins were examined in silico to study their effect on the three-dimensional structure of the protein.
Two mutations (p.His125Thrfs*8 and p.Leu463_Leu464dup) detected in patients with classic 11OHD showed a complete loss of P450c11 activity. The mutation (p.Ser150Leu) detected in a patient with non-classic 11OHD showed partial functional impairment with 19% of WT activity.
Functional mutation analysis enables the correlation of novel CYP11B1 mutations to the classic and non-classic 11OHD phenotype respectively. Mutations causing a non-classic phenotype show typically partial impairment due to reduced maximum reaction velocity comparable with non-classic mutations in 21-hydroxylase deficiency. The increasing number of mutations associated with non-classic 11OHD illustrate that this disease should be considered as diagnosis in patients with otherwise unexplained hyperandrogenism.
先天性肾上腺皮质增生症（CAH）是最常见的常染色体隐性遗传性内分泌疾病之一。类固醇11β-羟化酶（P450c11）缺乏症（11OHD）是CAH的第二常见形式。
本研究旨在探讨在11OHD患者中检测到的三种新型CYP11B1基因突变（p.His125Thrfs*8、p.Leu463_Leu464dup和p.Ser150Leu）的功能后果，并将这些数据与临床表型相关联。
通过使用HEK293细胞体外表达系统进行功能分析，比较野生型与突变型P450c11的活性。对突变蛋白进行计算机模拟分析，以研究其对蛋白质三维结构的影响。
在经典型11OHD患者中检测到的两种突变（p.His125Thrfs*8和p.Leu463_Leu464dup）显示P450c11活性完全丧失。在非经典型11OHD患者中检测到的突变（p.Ser150Leu）显示部分功能受损，活性为野生型的19%。
功能突变分析能够分别将新型CYP11B1突变与经典型和非经典型11OHD表型相关联。导致非经典型表型的突变通常表现为部分受损，这是由于最大反应速度降低所致，类似于21-羟化酶缺乏症中的非经典突变。与非经典型11OHD相关的突变数量不断增加，表明在患有不明原因高雄激素血症的患者中应考虑该病的诊断。
