Related Experiment Videos
CYP17 mutation E305G causes isolated 17,20-lyase deficiency by selectively altering substrate binding.
Daniel P Sherbet1, Dov Tiosano, Kerri M Kwist
1Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8857, USA.
The Journal of Biological Chemistry
|September 25, 2003
Summary
A specific mutation in cytochrome P450c17 (CYP17) impairs dehydroepiandrosterone synthesis, causing isolated 17,20-lyase deficiency. This genetic finding shows that androstenedione production alone is insufficient for complete male phenotype development.
Area of Science:
- Endocrinology
- Biochemistry
- Genetics
Background:
- Cytochrome P450c17 (CYP17) is crucial for androgen synthesis, catalyzing 17alpha-hydroxylase and 17,20-lyase reactions.
- Mutations in CYP17 can lead to combined or isolated deficiencies, impacting steroidogenesis and sexual development.
Purpose of the Study:
- To investigate the functional consequences of the CYP17 E305G mutation in an adolescent male with isolated 17,20-lyase deficiency.
- To elucidate the specific enzymatic activities affected by the E305G mutation and its impact on androgen precursor synthesis.
Main Methods:
- Expression of wild-type and E305G mutant CYP17 in HEK-293 cells and Saccharomyces cerevisiae.
- Biochemical assays to measure 17alpha-hydroxylase and 17,20-lyase activities using pregnenolone and progesterone as substrates.
Main Results:
- The E305G mutation retained 17alpha-hydroxylase activity but abolished 17,20-lyase activity for dehydroepiandrosterone (DHEA) synthesis via the delta5-steroid pathway.
- The mutation showed an 11-fold increased catalytic efficiency for androstenedione formation from 17alpha-hydroxyprogesterone (delta4-steroid pathway).
- The patient exhibited clinical features of isolated 17,20-lyase deficiency, including micropenis, hypospadias, and gynecomastia.
Conclusions:
- The E305G mutation selectively impairs DHEA synthesis, confirming its role in isolated 17,20-lyase deficiency.
- Androstenedione production through the delta4-steroid pathway alone is insufficient for the complete development of the male phenotype in humans.