title: Identification of steroid biosynthetic defects in genotype-proven heterozygous individuals for 17alpha-hydroxylase/17,20-lyase deficiency.
abstract: OBJECTIVE
  P450c17 deficiency (17alpha-hydroxylase/17,20-lyase deficiency, 17OHD) is a rare form of congenital adrenal hyperplasia caused by CYP17A1 gene mutations. The D487_F489 deletion in exon 8 and Y329fs in exon 6 are relatively frequent mutations of the CYP17A1 gene in China that completely abolish the enzyme activity of P450c17. However, little remains known about steroid biosynthetic functions in carriers with these mutations in a single allele of the CYP17A1 gene, who are assumed to have 50% P450c17 activity. We investigated adrenal steroidogenic function in genotype-proven heterozygotes carrying such mutations in the CYP17A1 gene in vivo.
  
  
  METHODS
  Eight patients and fourteen family members from five families with 17OHD were recruited. The mutations of the CYP17A1 gene in these individuals were screened by sequencing. The hormonal response to cosyntropin (ACTH) was evaluated in the 14 genotype-proven carriers and 45 age- and gender-matched normal controls.
  
  
  RESULTS
  Fourteen carriers of the CYP17A1 mutation - seven with the D487_F489 deletion, six with Y329fs and one with H373L - were identified from the five families with 17OHD. Compared with normal controls, carriers showed lower basal and ACTH-stimulated cortisol levels but higher ACTH-stimulated corticosterone levels. The ratios of corticosterone to cortisol in the genotype-proven heterozygotes were higher than those of the normal controls at the baseline and after cosyntropin stimulation. Similarly, the progesterone levels and the ratios of progesterone to 17-hydroxyprogesterone in the male heterozygotes were also higher than those of the normal controls, both before and after ACTH stimulation.
  
  
  CONCLUSIONS
  Genotype-proven carriers of the CYP17A1 mutation who lack apparent clinical symptoms exhibit decreased adrenal 17alpha-hydroxylase activity and altered adrenal gland reserve for steroid biosynthesis.
authors.affiliation: Department of Endocrinology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Qiao
authors.forename: Xia
authors.initials: X
authors.lastname: Chen
authors.forename: Chun-Lin
authors.initials: CL
authors.lastname: Zuo
authors.forename: Yan-Yun
authors.initials: YY
authors.lastname: Gu
authors.forename: Bing-Li
authors.initials: BL
authors.lastname: Liu
authors.forename: Jun
authors.initials: J
authors.lastname: Liang
authors.forename: Ying-Li
authors.initials: YL
authors.lastname: Lu
authors.forename: Jin-Feng
authors.initials: JF
authors.lastname: Tang
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Wu
authors.forename: Ming-Dao
authors.initials: MD
authors.lastname: Chen
authors.forename: Jia-Lun
authors.initials: JL
authors.lastname: Chen
authors.forename: Wan-Ling
authors.initials: WL
authors.lastname: Wu
authors.forename: Huai-Dong
authors.initials: HD
authors.lastname: Song
mesh_terms: D015062:11-Hydroxycorticosteroids / Q000097:blood*; D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000097:blood / Q000235:genetics*; D000328:Adult; D016022:Case-Control Studies; D003366:Cosyntropin; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006728:Hormones; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics*; D055815:Young Adult
chemical_list: D015062:11-Hydroxycorticosteroids; D006728:Hormones; D003366:Cosyntropin; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase