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Phenotype-Genotype Correlation in Eight Chinese 17-Hydroxylase/17,20 Lyase-Deficiency Patients with Five Novel Mutations of CYP17A1 Gene

Shanghai Clinical Center for Endocrine and Metabolic Diseases (J.Y., B.C., S.S., Y.B., J.L., Y.Z., J.C., G.N., X.L.), Shanghai Institute of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiaotong University Medical School, Institute of Health Science (B.C.), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Endocrine and Metabolic Division (G.N., X.L.), E-Institutes of Shanghai Universities, Shanghai 200025, People’s Republic of China; and Bioinformation Center (T.S., S.Z.), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, People’s Republic of China

Address all correspondence and requests for reprints to: G. Ning, M.D., Ph.D., and X. Li, M.D., Ph.D., Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiaotong University Medical School, Ruijin 2nd Road, Shanghai 200025, People’s Republic of China. E-mail: lixy{at}sibs.ac.cn.

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 17-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.