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Cited by 144Sexual Differentiation and DisordersAdrenal Hormones and DisordersMetabolism and Genetic Disorders

The syndrome of 17,20 lyase deficiency

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Miller, Walter L.·2012·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2011-2161PMC PMC3251937
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Abstract

CONTEXT: Disorders of steroidogenesis have been instrumental in delineating human steroidogenic pathways. Each genetic disorder seemed to correspond to a different steroidogenic activity, helping to identify several enzymes. Beginning in 1972, several patients have been reported as having "17,20 lyase deficiency," but there have been inconsistent genetic findings. OBJECTIVE: This manuscript reviews the biochemistry, genetics, and clinical disorders of 17,20 lyase activity, which converts 21-carbon precursors of glucocorticoids to 19-carbon precursors of sex steroids. FINDINGS: A single enzyme, cytochrome P450c17, catalyzes both 17α-hydroxylase activity and 17,20 lyase activity. The 17,20 lyase activity is especially sensitive to the activities of the accessory proteins P450 oxidoreductase and cytochrome b(5). The first cases of genetically and biochemically proven 17,20 lyase deficiency were reported in 1997, in which specific P450c17 mutations were identified that lost 17,20 lyase activity but not 17α-hydroxylase activity when assayed in vitro. Subsequent work identified other P450c17 mutations and mutations in the genes encoding P450 oxidoreductase and cytochrome b(5). Recently, the initially reported cases from 1972 were found to carry mutations in two aldo-keto reductases, AKR1C2 and AKR1C4. These AKR1C isozymes catalyze 3α-hydroxysteroid dehydrogenase activity in the so-called "backdoor pathway" by which the fetal testis produces dihydrotestosterone without the intermediacy of testosterone. CONCLUSIONS: 17,20 Lyase deficiency should be considered a syndrome with multiple causes, and not a single disease. Study of this very rare disorder has substantially advanced our understanding of the pathways, mechanisms, and control of androgen synthesis. Mutations in other, as-yet unidentified genes may also cause this phenotype.

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  • Regulation of 17,20-lyase activity, and consequently of androgen production, depends on factors that facilitate the flow of electrons to P450c17: high concentrations of POR, the presence of b5, and serine phosphorylation of P450c17.

    “Thus, the regulation of 17,20-lyase activity, and consequently of androgen production, depends on factors that facilitate the flow of electrons to P450c17: high concentrations of POR, the presence of b5, and serine phosphorylation of P450c17”

    From Steroidogenic electron-transfer factors and their diseases (2021) · cites this paper as [105]

  • b5 deficiency is an important cause of 17,20-lyase deficiency that does not appear to affect cortisol synthesis, whereas specific P450c17 mutations and the one reported POR mutation that presented as 17,20-lyase deficiency may have residual cortisol synthesis.

    “Thus, b5 deficiency is an important cause of 17,20-lyase deficiency that does not appear to affect cortisol synthesis, whereas specific P450c17 mutations and the one reported POR mutation that presented as 17,20-lyase deficiency [ 64 ] may have residual cortisol synthesis”

    From Steroidogenic electron-transfer factors and their diseases (2021) · cites this paper as [105]

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Authors
Miller, W. L.
Affiliations
University of California, San Francisco (US)
Corresponding author
Miller, Walter L.
ORCID
Miller, Walter L.
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2012-01
Volume
97
Issue
1
Pages
59-67
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2011-2161
PMC
PMC3251937
OpenAlex
W2001518235
Cited by
143
References
82
Citations by year
2026: 5 · 2025: 9 · 2024: 24 · 2023: 5 · 2022: 5 · 2021: 10 · 2020: 10 · 2019: 13 · 2018: 5 · 2017: 9 · 2016: 6 · 2015: 13 · 2014: 15 · 2013: 10 · 2012: 3
FWCI
0.81
Type
journal article
Language
en
Open access
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • University of California, San Francisco
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK-37922, R01DK037922)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
17,20-lyase deficiency, steroidogenesis disorders, P450c17, cytochrome P450 oxidoreductase, cytochrome b5, AKR1C2, AKR1C4, 3α-hydroxysteroid dehydrogenase, androgen production, dihydrotestosterone
MeSH terms
Adrenal Hyperplasia, Congenital, Humans, Hydroxysteroid Dehydrogenases, Models, Biological, Mutation, Oxidoreductases, Steroid 17-alpha-Hydroxylase, Syndrome, Cytochromes b5, 3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)

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