Mutational spectrum of the steroid 21-hydroxylase gene in Austria:: Identification of a novel missense mutation
Mutational spectrum of the steroid 21-hydroxylase gene in Austria:: Identification of a novel missense mutation
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DOI：
10.1210/jc.86.10.4771
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发表时间：
2001-10-01
影响因子：
5.8
通讯作者：
Vierhapper, H
中科院分区：
文献类型：
--
作者：
Baumgartner-Parzer, SM;Schulze, E;Vierhapper, H
本研究试图在79个无关的奥地利患者的经典和非经典形式的先天性肾上腺皮质增生症和他们各自的112个家庭成员的21-羟化酶缺乏症的突变谱进行分析。在158个无关的先天性肾上腺皮质增生等位基因中，31%存在明显的大基因缺失/转换，而最常见的点突变是内含子2剪接（22.8%）、I172 N（15.8%）、V281 L（12%）和P30 L（7.6%），与其他国家报告的频率一致。在12个携带P30 L突变的先天性肾上腺皮质增生等位基因中，有5个基因的畸变是基于单碱基取代，而其余7个基因的畸变是CYP 21 B转换的一部分（I等位基因）或CYP 21 B/21 A杂合基因（6个等位基因），后者的特征是在内含子2之前有一个连接位点，如Southern印迹，PCR，和序列分析。先前描述的突变不存在于1.2%不相关的先天性肾上腺增生等位基因中，其中包括一名出现严重生殖器男性化的女性患者。完整的功能性21-羟化酶基因的序列分析揭示了外显子10-Arg（426）His中尚未描述的突变，该突变尚未被描述为代表常见的假基因序列。体外表达实验表明，Arg（426）His突变体对天然底物17-羟孕酮仅表现出低酶活性，这与发现该突变体的患者的疾病表现程度相对应。
This study attempted an analysis of the mutational spectrum of 21-hydroxylase deficiency in 79 unrelated Austrian patients with classical and nonclassical forms of congenital adrenal hyperplasia and their respective 112 family members. Apparent large gene deletions/conversions were present in 31% of the 158 unrelated congenital adrenal hyperplasia alleles, whereas the most frequent point mutations were intron 2 splice (22.8%),I172N (15.8%), V281L (12%), and P30L (7.6%), in line with the frequencies reported for other countries. In 5 of the 12 congenital adrenal hyperplasia alleles carrying a P30L mutation the aberration is based on a single base substitution, whereas the remaining 7 represent part of a CYP21B conversion (I allele) or CYP21B/21A hybrid gene (6 alleles), the latter characterized by a junction site before intron 2 as indicated by Southern blot, PCR, and sequence analyses.Previously described mutations were not present in 1.2% of unrelated congenital adrenal hyperplasia alleles, including one female patient presenting with severe genital virilization. Sequence analysis of the complete functional 21-hydroxylase gene revealed an as yet undescribed mutation in exon 10-Arg(426)His, which has not yet been described to represent a common pseudogene sequence. In vitro expression experiments showed the Arg(426)His Mutant to exhibit only low enzyme activity toward the natural substrate 17-hydroxyprogesterone corresponding to the degree of disease manifestation in the patient in whom it was found.