Three novel CYP21A2 mutations and their protein modelling in patients with classical 21-hydroxylase deficiency from northeastern Iran
Three novel CYP21A2 mutations and their protein modelling in patients with classical 21-hydroxylase deficiency from northeastern Iran
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DOI：
10.1111/j.1365-2265.2007.02886.x
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发表时间：
2007-09-01
影响因子：
3.2
通讯作者：
Abbaszadegan, Mohammad Reza
中科院分区：
文献类型：
--
作者：
Baradaran-Heravi, Alireza;Vakili, Rahim;Abbaszadegan, Mohammad Reza
先天性肾上腺皮质增生（CAH）是一组常染色体隐性遗传疾病，常由类固醇21-羟化酶基因（CYP 21 A2）突变引起。我们描述了三个新的CYP 21 A2突变CAH patients. The整个CYP 21 A2基因的序列分析，然后进行分子建模在三个无关的经典CAH患者的伊朗东北部的起源。在两名具有盐耗（SW）表型的女性患者中发现了两个新的错义突变，外显子9的F404 S和外显子10的T450 P，均为纯合子。通过等位基因特异性聚合酶链反应（PCR）筛选这些新的变体，并排除在100个无关的正常等位基因。基于分子建模和序列保守性的临床严重性预测与携带这些突变的患者的临床诊断密切相关。第三个新的突变，外显子1，g.19_28del的一个小的10-bp的缺失，被发现在一个女性患者与一个简单的男性化表型的复合杂合子形式与常见的内含子2剪接突变（IVS 2 - 13 A/C > G）。这种移码突变导致氨基酸位置48处的提前终止密码子L48 X，导致无功能蛋白质。在CYP 21 A2基因中发现了3个新的突变，这些突变被预测会严重损害酶活性，导致严重的经典CAH。这些突变均不发生在CYP 21 A1 P假基因中。
Congenital adrenal hyperplasia (CAH) refers to a group of autosomal recessive disorders frequently caused by mutations in the steroid 21-hydroxylase gene (CYP21A2). We describe three novel CYP21A2 mutations in CAH patients.Sequence analysis of the entire CYP21A2 gene followed by molecular modelling was performed in three unrelated classical CAH patients of northeastern Iranian origin. The active (CYP21A2) and pseudogene (CYP21A1P) alleles were screened for the presence of the new variations in controls.Two novel missense mutations, F404S in exon 9 and T450P in exon 10, were found in homozygous forms in two female patients with a salt-wasting (SW) phenotype. These novel variants were screened by allele-specific polymerase chain reaction (PCR) and excluded in 100 unrelated normal alleles. Prediction of clinical severity, based on molecular modelling and sequence conservation, correlates well with the clinical diagnosis of the patients carrying these mutations. The third novel mutation, a small 10-bp deletion in exon 1, g.19_28del, was found in a female patient with a simple virilizing phenotype in a compound heterozygous form with the common intron 2 splice mutation (IVS2-13A/C > G). This frameshift mutation causes a premature stop codon at amino acid position 48, L48X, resulting in a nonfunctional protein. The CYP21A1P pseudogene alleles were also screened and none of these novel mutations could be detected.Three novel mutations were found in the CYP21A2 gene and predicted to drastically impair enzyme activity resulting in severe classic CAH. None of these mutations occurs in the CYP21A1P pseudogene.