Rare hypertension as a result of 17alpha-hydroxylase deficiency.

PURPOSE: To investigate CYP 7A1 gene mutations in Chinese patients with 17alpha-hydroxylase deficiency. METHODS: Clinical data were retrospectively analyzed. CYP17A1 mutations were detected in two cases with 17alpha-hydroxylase deficiency. Genomic DNA was isolated from blood samples and eight primers pairs were used to amplify eight exons and exon-intron boundaries of the CYP17A1 gene. The amplified PCR products were purified by agarose gel electrophoresis and then directly sequenced. Sequencing results were compared to the established human CYP17A1 sequence. RESULTS: Two compound mutations were identified: TAC --> AA at codons 436-438 on exon 6, causing the amino acid missense mutation Y329K/418X; and deletion of the 9-bp sequence GACTCTTTC at codons 487-489 on exon 8, causing deletion of three amino acids (Asp-Ser-Phe). CONCLUSION: D487_F489del and Y329K, 418X CYP17A1 mutations were identified in our two patients. A literature review revealed that the main CYP17A1 mutations in the Chinese population are missense and splicing defects, and exons 8 and 6 are most frequently involved.

Phenotype-genotype correlation in eight Chinese 17alpha-hydroxylase/17,20 lyase-deficiency patients with five novel mutations of CYP17A1 gene.

CONTEXT: 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. OBJECTIVE: The objective of the study was to explore the phenotype-genotype correlation in patients with subtle and classic manifestations. SUBJECTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.