Yang Jun, Cui Bin, Sun Shouyue, Shi Tieliu, Zheng Siyuan, Bi Yufang, Liu Jianmin, Zhao Yongju, Chen Jialun, Ning Guang, Li Xiaoying
Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiaotong University Medical School, Ruijin 2nd Road, Shanghai 200025, People's Republic of China.
J Clin Endocrinol Metab. 2006 Sep;91(9):3619-25. doi: 10.1210/jc.2005-2283. Epub 2006 Jun 13.
P450c17 deficiency (17OHD), caused by mutation in CYP17A1 gene, is characterized by severe hypertension-hypokalemia, sexual infantilism in females, and pseudohermaphroditism in males. We investigated eight Chinese 17OHD patients with five novel mutations of CYP17A1 gene and analyzed phenotype-genotype correlation in a patient with regular menses and seven others with classic presentations by in vitro expression and computer modeling.
The objective of the study was to explore the phenotype-genotype correlation in patients with subtle and classic manifestations.
Eight patients with 17OHD from seven families were diagnosed according to clinical manifestations and basal hormone assays. The CYP17A1 gene was amplified and sequenced. Haplotyping analysis was performed to determine a common ancestor for those subjects with a frequent mutation 1517_1525del. In vitro enzymatic activities assay and computer modeling were used to analyze the phenotype-genotype correlation.
Five novel CYP17A1 mutations, homozygous D487_F489del (1517_1525del) and F453S, combined compound Y329K and 1047del, P434L and V310_W313del, and R416C and D487_F489del were identified. Haplotyping showed that 1517_1525del might be inherited from a common ancestor. Compared with the mutations in patients with classical manifestations, F453S in the patient with regular menses, occasional hypertension, and hypokalemia showed a partially reduced 17alpha-hydroxylase (29% of those of wild type) and a minor protein conformational change.
The clinical manifestations in patients with 17OHD correlate with CYP17A1 mutations and enzymatic activities by in vitro enzyme assay and computer modeling. F453S mutation results in partially reduced enzymatic activities and a subtle phenotype. The prevalent mutation 1517_1525del in Chinese 17OHD patients might be a founder effect.
由CYP17A1基因突变引起的P450c17缺乏症（17OHD）的特征为严重的高血压 - 低钾血症、女性性幼稚症以及男性假两性畸形。我们研究了8例携带CYP17A1基因5种新突变的中国17OHD患者，并通过体外表达和计算机建模分析了1例月经规律患者和7例典型表现患者的表型 - 基因型相关性。
本研究的目的是探索具有轻微和典型表现的患者的表型 - 基因型相关性。
根据临床表现和基础激素检测，诊断了来自7个家庭的8例17OHD患者。对CYP17A1基因进行扩增和测序。进行单倍型分析以确定具有常见突变1517_1525del的受试者的共同祖先。使用体外酶活性测定和计算机建模来分析表型 - 基因型相关性。
鉴定出5种新的CYP17A1突变，纯合子D487_F489del（1517_1525del）和F453S，复合突变Y329K和1047del、P 434L和V310_W313del，以及R416C和D487_F489del。单倍型分析表明1517_1525del可能从共同祖先遗传而来。与具有典型表现患者的突变相比，月经规律、偶发高血压和低钾血症患者中的F453S显示17α - 羟化酶部分降低（为野生型的29%）且蛋白质构象变化较小。
17OHD患者的临床表现与CYP17A1突变以及通过体外酶测定和计算机建模得出的酶活性相关。F453S突变导致酶活性部分降低和轻微表型。中国17OHD患者中常见的突变1517_1525del可能是奠基者效应。
