Centre for Endocrinology, Diabetes, and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Institute of Biomedical Research, Wolfson Drive, Birmingham B15 2TT, United Kingdom.
J Clin Endocrinol Metab. 2011 Nov;96(11):E1798-806. doi: 10.1210/jc.2011-1277. Epub 2011 Aug 31.
Cytochrome P450 side-chain cleavage enzyme (CYP11A1) facilitates the first and rate-limiting step of steroidogenesis. Only nine patients with CYP11A1 deficiency have been described. All patients presented with adrenal insufficiency (AI) and disorder of sex development in 46,XY individuals.
Our objective was to define the pathogenic consequences of a novel CYP11A1 mutation (p.R451W) found in two brothers with isolated adrenal insufficiency.
The two brothers (46,XY) presented with AI and normal male genital development. The older boy first presented with signs and symptoms suggestive of AI at the age of 2.8 yr but was only diagnosed at the age of 4.1 yr during an adrenal crisis. The younger brother was diagnosed with AI at the age of 2.5 yr while being clinically asymptomatic. Both boys had entirely normal appearance of their external genitalia.
The novel p.R451W mutation and five published missense CYP11A1 mutations were characterized employing two in vitro approaches using the natural substrate cholesterol and the intermediate 22R-hydroxycholesterol, respectively. Pregnenolone generation was measured by highly specific liquid chromatography tandem mass spectrometry. p.R451W had 30% of wild-type activity consistent with the clinical phenotype in our patients. Two previously published mutations (p.L222P and p.A359V) had 2- to 3-fold higher in vitro activities than originally reported, correlating better with the associated phenotypes.
We provide the first evidence that partial CYP11A1 deficiency has to be considered as a differential diagnosis in clinically isolated adrenal insufficiency. Our assays demonstrate a tighter genotype-phenotype correlation in CYP11A1 deficiency than previous in vitro studies.
细胞色素 P450 侧链裂解酶（CYP11A1）促进类固醇生成的第一步和限速步骤。仅有 9 例 CYP11A1 缺乏症患者被描述过。所有患者均表现为肾上腺皮质功能不全（AI）和 46,XY 个体的性别发育障碍。
我们的目的是定义在两名孤立性肾上腺皮质功能不全的兄弟中发现的新型 CYP11A1 突变（p.R451W）的致病后果。
这两兄弟（46,XY）表现为 AI 和正常男性外生殖器发育。年龄较大的男孩首次在 2.8 岁时出现 AI 的症状和体征，但直到 4.1 岁时因肾上腺危象才被诊断。年龄较小的男孩在 2.5 岁时被诊断为 AI，但无症状。两名男孩的外生殖器外观均完全正常。
采用两种体外方法，分别使用天然底物胆固醇和中间产物 22R-羟胆固醇，对新型 p.R451W 突变和五名已发表的 CYP11A1 错义突变进行了特征描述。通过高度特异性的液相色谱串联质谱法测量 pregnenolone 的生成。p.R451W 的活性为野生型的 30%，与我们患者的临床表现一致。以前报道的两种突变（p.L222P 和 p.A359V）的体外活性比最初报道的高 2-3 倍，与相关表型的相关性更好。
我们首次提供了证据表明，在临床上孤立性肾上腺皮质功能不全中，应考虑部分 CYP11A1 缺乏症作为鉴别诊断。我们的检测比以前的体外研究更紧密地将基因型与表型联系起来。
