Abstract | CONTEXT: OBJECTIVE: DESIGN: We investigated the clinical and biochemical phenotype, conducted genetic analyses, and functionally characterized the identified CYB5A mutation in cell-based CYP17A1 coexpression assays. RESULTS: All three siblings presented with 46,XY DSD, sex steroid deficiency, normal mineralocorticoids and glucocorticoids, and a urine steroid metabolome suggestive of isolated 17,20 lyase deficiency. CYP17A1 and POR sequences were normal, but we detected a homozygous CYB5A missense mutation (g.28,400A→T; p.H44L). Functional in vitro analysis revealed normal CYP17A1 17α-hydroxylase activity but severely impaired 17,20 lyase activity. In silico analysis suggested the disruption of CYB5A heme binding by p.H44L. CONCLUSION: We have identified the first human CYB5A missense mutation as the cause of isolated 17,20 lyase deficiency in three individuals with 46,XY DSD. Detailed review of previously reported cases with apparently isolated 17,20 lyase deficiency due to mutant CYP17A1 and POR reveals impaired 17α-hydroxylase activity as assessed by steroid metabolome analysis and short cosyntropin testing. This suggests that truly isolated 17,20 lyase deficiency is observed only in individuals with inactivating CYB5A mutations.
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Authors | Jan Idkowiak, Tabitha Randell, Vivek Dhir, Pushpa Patel, Cedric H L Shackleton, Norman F Taylor, Nils Krone, Wiebke Arlt |
Journal | The Journal of clinical endocrinology and metabolism
(J Clin Endocrinol Metab)
Vol. 97
Issue 3
Pg. E465-75
(Mar 2012)
ISSN: 1945-7197 [Electronic] United States |
PMID | 22170710
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Cytochromes b5
- CYP17A1 protein, human
- Steroid 17-alpha-Hydroxylase
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Topics |
- Adolescent
- Adrenal Hyperplasia, Congenital
(enzymology, genetics)
- Child
- Child, Preschool
- Cytochromes b5
(genetics, metabolism)
- Disorder of Sex Development, 46,XY
(enzymology, genetics)
- Humans
- Infant
- Infant, Newborn
- Mutation, Missense
- Steroid 17-alpha-Hydroxylase
(metabolism)
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