基因型明确的17α-羟化酶／17，20-裂解酶缺陷症杂合子肾上腺皮质功能的研究

Identification of steroid biosynthetic defects in genotype-proven heterozygote individuals with 17α-hydroxylase/17,20-1yase deficiency

目的明确携带CYP17A1基因突变的杂合子个体肾上腺类固醇激素合成功能。方法对17α-羟化酶和17，20-裂解酶缺陷（170HD）5个家系的8例患者和14例家系成员，通过PCR产物直接测序的方法来鉴定CYP17A1基因突变，并测定CYP17A1基因突变携带者与45名年龄、性别匹配的正常个体在ACTH兴奋前后肾上腺皮质激素的变化。结果发现5个家系14例CYP17A1基因突变的携带者中，7例为13487_F489del，6例为Y329fs，1例为H373L。杂合携带者基础和ACTH刺激后的皮质醇水平均低于正常对照，而兴奋后的皮质酮水平高于正常。杂合子的皮质酮与皮质醇的比值在ACTH兴奋前后皆高于正常对照。而男性杂合子在ACTH兴奋前后孕酮水平以及孕酮与17-羟孕酮比值也均都高于正常对照。D487_F489del和Y329fs两组杂合子之间的激素水平无显著差异。结论与CYP21A2基因突变的携带者体内的21-羟化酶活性轻度受损相类似，CYP17A1基因突变杂合携带者的肾上腺类固醇激素合成已有异常。

Objective To investigate the adrenal steroidogenic function in genotype-proven heterozygotes carrying mutations in CYP17A1 gene in viva. Methods Eight patients and 14 family members from 5 families with 17-hydroxylase/17,20-1yase deficiency （17OHD） were recruited. The mutations of the CYP17A1 gene in these individuals were screened by direct sequencing of PCR products. The hormonal response to ACTH was evaluated in the 14 genotype-proven carriers and 45 age-and sex-matched normal subjects. Results Three mutations were found in 5 unrelated families. 14 carriers with CYP17A1 mutation were identified, including 7 heterozygotes with D487 F489del, 6 with Y329fs, and 1 for H373L. Compared to the normal subjects, the carriers exhibited lower basal and ACTH-stimulated cortisol levels, but higher ACTH-stimulated corticosterone level. The ratios of corticosterone to cortisol in the gcnotype-proven heterozygotes were higher than those of normal individuals at baseline and following ACTH-stimulation. Similarly, progesterone level and ratios of progesterone to 17-hydroxyprogesterone in the male heterozygotes were also higher than that of normal individuals before and after stimulation. No significant differences were observed in the hormone levels between two genotypes （D487 F489del vs Y329fs）. Conclusions Genotype-proven carriers of 170HD without apparent clinical symptoms exhibit decreased enzyme activity, analogous to mildly impaired adrenal 21-hydroxylase activity in the carriers of CYP21 A2 gene mutation.