Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Identification of a Functional Polymorphism of the Human Type 5 17{beta}-Hydroxysteroid Dehydrogenase Gene Associated with Polycystic Ovary Syndrome Qin K, et al . Context. Polycystic ovary syndrome (PCOS) is characterized by chronic hyperandrogenic anovulation and is associated with insulin resistance. Its pathogenesis is believed to be multifactorial, and abnormal gene regulation could be one contributing factor. Type 5 17 beta-hydroxysteroid dehydrogenase (17beta-HSD5) appears to be the major testosterone-forming 17beta-HSD isoenzyme in females. Objective. To investigate the role of a potentially activating 17beta-HSD5 gene (HSD17B5) variant in hyperandrogenism. Design. Case report and case-control cohort study. Setting. General Clinical Research Center. Study subjects. A case of PCOS who had hyperthecosis associated with profound type B insulin resistance and an unusual, frankly male, testosterone response to a gonadotropin releasing hormone agonist test, 121 PCOS, and 128 population controls. Interventions. Diagnostic. Main outcome measures. Sequencing of HSD17B5 5'-flanking region and 9 exons, genotype/phenotype studies, and in vitro functional studies. Results. Our case had a previously undescribed homozygous HSD17B5 variant (G-to-A substitution) -71 bp in the promoter region. Genotyping controls showed this to be a single nucleotide polymorphism (SNP-71G). Luciferase activity of a SNP-71G promoter construct was significantly higher than that of the wild-type, and electrophoretic mobility shift assays revealed that SNP-71G possessed significantly increased affinity to nuclear transcription factors. SNP-71G allele frequency (32.2% vs. 22.3%) and SNP-71G allele homozygosity (10.7% vs. 6.25%) were significantly increased in PCOS (P = 0.012). SNP-71G homozygosity tended to contribute about 20% to the plasma testosterone level. Conclusions. SNP-71G is a functional polymorphism that may contribute to testosterone excess in a subset of PCOS patients.