Clinical and molecular manifestation of fifteen 17OHD patients: a novel mutation and a founder effect
Clinical and molecular manifestation of fifteen 17OHD patients: a novel mutation and a founder effect
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15 名 17OHD 患者的临床和分子表现：一种新的突变和创始人效应
DOI：
10.1007/s12020-016-0957-y
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发表时间：
2016-09-01
期刊：
影响因子：
3.7
通讯作者：
Qiao, Jie
中科院分区：
文献类型：
--
作者：
Han, Bing;Xue, Liqiong;Qiao, Jie
17-羟化酶缺乏症（17 OHD）长期以来被认为是一种罕见的先天性肾上腺皮质增生症，以常染色体隐性模式遗传。本文对15例17例OHD患者的临床表现及激素水平进行了描述。然后对1例新患者的CYP 17 A1基因进行扩增和测序。杂合突变C。431_433del，p.K144del/c.鉴定出985_987delinsAA，p.Y329 fs。功能研究表明，新突变K144 del完全消除酶活性。在三维模型中，K144 del突变完全破坏了类固醇结合结构域中的α螺旋。选取CYP 17 A1基因内16个SNPs，在7个无关家系中进行基因分型，以确定Y329 fs在中国是否具有奠基者效应。单倍型分析表明，所有的c。985_987delinsAA突变具有相同的单倍型。然而，从2760名对照的GWAS数据中，仅在一条染色体上发现了这种特殊的单倍型。总之，我们从1例17 OHD患者中发现了一种新的（K144 del）和一种广泛报道的（Y329 fs）CYP 17 A1基因杂合突变。单倍型分析表明，中国人常见的突变Y329 fs来自同一祖先，这解释了17 OHD是中国CAH第二位病因的原因。
17-hydroxylase deficiency (17OHD) has long been regarded as a rare form of congenital adrenal hyperplasia, inherited in an autosomal recessive pattern. Fifteen patients with 17OHD were described from clinical manifestations and hormone profile. Then,CYP17A1gene was amplified and sequenced in a new patient. Heterozygous mutations c. 431_433del, p.K144del/c. 985_987delinsAA, p.Y329 fs were identified. Functional study indicated the novel mutation K144del completely abolished enzyme activity. In the three-dimensional model, the K144del mutation completely destroyed the alpha helix in the steroid binding domain. Sixteen SNPs withinCYP17A1gene were selected and genotyped in 7 unrelated families to determine whether Y329 fs had founder effect in China. Haplotyping study showed that all c. 985_987delinsAA mutation shared the same haplotype. However, from GWAS data of 2760 controls, this special haplotype was found only in one chromosome. In conclusion, we identified a novel (K144del) and a widely reported (Y329 fs) heterozygous mutations ofCYP17A1gene from a 17OHD patient. Haplotyping analysis showed the common mutation Y329 fs in China came from the same ancestor, which explains the reason that 17OHD was the second cause of CAH in China.