Cytochrome P450 oxidoreductase gene mutations and Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis: Molecular and clinical studies in 10 patients
Cytochrome P450 oxidoreductase gene mutations and Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis: Molecular and clinical studies in 10 patients
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DOI：
10.1210/jc.2004-0810
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发表时间：
2005-01-01
影响因子：
5.8
通讯作者：
Ogata, T
中科院分区：
文献类型：
--
作者：
Fukami, M;Horikawa, R;Ogata, T
我们报告了来自8个家庭的10名日本患者(4名男性和6名女性)的分子和临床表现，这些患者来自8个家庭(2对兄弟姐妹和6个孤立病例)，伴有生殖器异常和/或类固醇激素合成障碍。对细胞色素P450氧化还原酶基因(POR)的15个外显子进行了直接测序，发现有两个错义突变(R457H和Y578C)，一个24bp的缺失突变导致9个氨基酸缺失而产生一个氨基酸(L612_W620delinsR)，一个单一的BP插入突变导致移码(I444fsX449)，以及一个沉默突变(G5G)。R457H此前已被证明是一种病理突变，计算机模拟分析表明，G5G的15A和GT；G可能干扰外显子剪接增强基序，其余三个突变应该影响蛋白质的构象。6例为复合杂合子，3例为R457H纯合子，其余1例未发现1个等位基因突变。临床表现包括不同程度的骨骼特征，如男女患者的短头畸形、放射肱骨融合和指关节挛缩，男性患者在胎儿和青春期男性化正常到较差，女性患者在胎儿时期男性化和青春期发育不良而不恶化男性化，男女患者从青春期开始的身高增长和骨龄延迟，以及孕期母体男性化。血液胆固醇总体正常，内分泌研究显示CYP17A1和CYP21A2活性有缺陷。结果提示，伴有生殖器异常和/或类固醇合成障碍的Antley-Bixler综合征是由POR突变引起的，其临床特征是多种多样的，主要由POR依赖的CYP51A1、CYP17A1、CYP21A2和CYP19A1的活性受损解释。
We report on molecular and clinical findings in 10 Japanese patients ( four males and six females) from eight families ( two pairs of siblings and six isolated cases) with Antley-Bixler syndrome accompanied by abnormal genitalia and/or impaired steroidogenesis. Direct sequencing was performed for all the 15 exons of cytochrome P450 oxidoreductase gene (POR), showing two missense mutations (R457H and Y578C), a 24-bp deletion mutation resulting in loss of nine amino acids and creation of one amino acid (L612_W620delinsR), a single bp insertion mutation leading to frameshift (I444fsX449), and a silent mutation (G5G). R457H has previously been shown to be a pathologic mutation, and computerized modeling analyses indicated that the 15A>G for G5G could disturb an exonic splicing enhancer motif, and the remaining three mutations should affect protein conformations. Six patients were compound heterozygotes, and three patients were R457H homozygotes; no mutation was identified on one allele of the remaining one patient. Clinical findings included various degrees of skeletal features, such as brachycephaly, radiohumeral synostosis, and digital joint contractures in patients of both sexes, normal-to-poor masculinization during fetal and pubertal periods in male patients, virilization during fetal life and poor pubertal development without worsening of virilization in female patients, and relatively large height gain and delayed bone age from the pubertal period in patients of both sexes, together with maternal virilization during pregnancy. Blood cholesterol was grossly normal, and endocrine studies revealed defective CYP17A1 and CYP21A2 activities. The results suggest that Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis is caused by POR mutations, and that clinical features are variable and primarily explained by impaired activities of POR-dependent CYP51A1, CYP17A1, CYP21A2, and CYP19A1.