R339H and P453S: CYP21 mutations associated with nonclassic steroid 21-hydroxylase deficiency that are not apparent gene conversions.
Open accessAbstract
Steroid 21-hydroxylase deficiency is the most common enzymatic defect causing congenital adrenal hyperplasia, an inherited disorder of cortisol biosynthesis. All mutations thus far characterized that cause this disorder appear to result from recombinations between the gene encoding the enzyme, CYP21B (CYP21), and the adjacent pseudogene, CYP21A (CYP21P). These are either deletions caused by unequal crossing-over during meiosis or apparent transfers of deleterious sequences from CYP21A to CYP21B, a phenomenon termed gene conversion. However, a small percentage of alleles do not carry such a mutation. We analyzed DNA from a patient with the mild, nonclassic form of 21-hydroxylase deficiency, who carried one allele that had no gene conversions detectable by hybridization with oligonucleotide probes. Sequence analysis revealed that this allele carried two missense mutations, R339H and P453S, neither of which has been previously observed in CYP21A or CYP21B. Each of these mutations was introduced into CYP21 cDNA which was then expressed in COS1 cells using a vaccinia virus system. Each mutation reduced the ability of the enzyme to 21-hydroxylate 17-hydroxyprogesterone to 50% of normal and the ability to metabolize progesterone to 20% of normal. Thus, each of these mutations represents a potential nonclassic 21-hydroxylase deficiency allele that is not the result of an apparent gene conversion.
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The simulation results provided qualitative, yet quantitatively characterized, agreement with the reported clinical phenotype of CAH patients: mild CAH patients have often been reported to be asymptomatic or to have signs of androgen excess with around 10-fold higher ACTH morning peak, while severe CAH patients have even more pronounced excess androgen production with around 100-fold higher ACTH.
“Patients with mild CAH have been often reported to be asymptomatic (cortisol concentrations following similar trajectories throughout the day) or with signs of androgen excess (increased ACTH, around 10-fold higher morning peak), while for patients with severe CAH excess androgen production was even more pronounced (increased ACTH, around 100-fold higher morning peak) [4, 6, 31, 32].”
From A quantitative modeling framework to understand the physiology of the hypothalamic-pituitary-adrenal axis and interaction with cortisol replacement therapy (2024) · cites this paper as [32]
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Experimental — accuracy not yet measuredPatients with P450c21 variants (e.g., the common P30L and V281L mutations and less common R339H and P453S), which have 20 to 50% of wild-type activity, can have various phenotypes, implying additional factors that can modify the clinical manifestations of 21-hydroxylase deficiency.
“In contrast, patients with P450c21 variants [e.g., the common P30L (363) and V281L mutations and less common mutations R339H and P453S], which have 20 to 50% of wild-type activity (352, 364), can have various phenotypes, implying additional factors that can modify the clinical manifestations of 21-hydroxylase deficiency.”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [364]
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Experimental — accuracy not yet measuredMutations R339H and P453S have been associated with nonclassical CAH.
“In addition, the mutations R339H and P453S have been associated with nonclassical CAH (364,445).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [364]
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References 12 · Cited by 123
- Authors
- Helmberg, A., Tusie-Luna, M. T., Tabarelli, M., Kofler, R., & White, P. C.
- Affiliations
- Innsbruck Medical University (AT)
- ORCID
- White, P C
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 1992-08
- Volume
- 6
- Issue
- 8
- Pages
- 1318-1322
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- OpenAlex
- W2012819681
- Cited by
- 123
- References
- 12
- Citations by year
- 2024: 2 · 2023: 2 · 2022: 2 · 2021: 2 · 2020: 1 · 2019: 4 · 2018: 1 · 2017: 3 · 2016: 1 · 2015: 1 · 2014: 3 · 2013: 1 · 2012: 3
- FWCI
- 2.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Charles H. Revson Foundation
- National Institutes of Health (10021)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-37867)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 00072)
- 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
- 21-hydroxylase deficiency, non-classical congenital adrenal hyperplasia, CYP21 mutations, missense mutations, gene conversion, unequal crossover, progesterone metabolism, enzyme activity
- MeSH terms
- Adrenal Hyperplasia, Congenital, Adult, Alleles, Amino Acid Sequence, Base Sequence, Cloning, Molecular, Female, Gene Conversion, Humans, Molecular Sequence Data, Recombinant Proteins, Steroid 21-Hydroxylase, Polymerase Chain Reaction, Mutagenesis, Site-Directed, Point Mutation, Sequence Homology, Amino Acid
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