Gene conversions and unequal crossovers between CYP21 (steroid 21-hydroxylase gene) and CYP21P involve different mechanisms
Open accessAbstract
Most cases of congenital adrenal hyperplasia, the inherited inability to synthesize cortisol, are caused by mutations in the steroid 21-hydroxylase gene (CYP21). Steroid 21-hydroxylase deficiency is unusual among genetic diseases in that approximately 95% of the mutant alleles have apparently been generated by recombination between a normally active gene (CYP21) and a linked pseudogene (CYP21P). Approximately 20% of mutant alleles carry DNA deletions of 30 kb that have presumably been generated by unequal meiotic crossing-over, whereas 75% carry one or more mutations in CYP21 that are normally found in the CYP21P pseudogene. These latter mutations are termed "gene conversions," although the mechanism by which they are generated is not well understood. To assess the frequency at which these different recombination events occur, we have used PCR to detect de novo deletions and gene conversions in matched sperm and peripheral blood leukocyte DNA samples from normal individuals. Deletions with breakpoints in a 100-bp region in intron 2 and exon 3 were detected in sperm DNA samples with frequencies of approximately 1 in 10(5)-10(6) genomes but were never detected in the matching leukocyte DNA. Gene conversions in the same region occur in approximately 1 in 10(3)-10(5) genomes in both sperm and leukocyte DNA. These data suggest that whereas deletions occur exclusively in meiosis, gene conversions occur during both meiosis and mitosis, or perhaps only during mitosis. Thus, gene conversions must occur by a mechanism distinct from unequal crossing-over.
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Additional relevant transcription factors include nerve growth factor induced-B and Nur-related factor 1, which may overlap in their functions.
“Additional relevant transcription factors include nerve growth factor induced-B (NGFI-B, Nur77, NR4A1)(169,184), and Nur-related factor 1 (NURR1) (NR4A2); they may overlap in their functions (185).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [185]
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- Authors
- Tusié-Luna, M. T., & White, P. C.
- Affiliations
- Unidad de Genética de la Nutrición-Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México-Instituto Nacional de Pediatriá, Mexico D.F.
- Instituto Nacional de Pediatria (MX)
- ORCID
- White, P C
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1995-11-07
- Volume
- 92
- Issue
- 23
- Pages
- 10796-10800
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC40699
- OpenAlex
- W2088237310
- Cited by
- 179
- References
- 4
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 5 · 2023: 3 · 2022: 4 · 2021: 3 · 2020: 2 · 2019: 3 · 2018: 2 · 2017: 3 · 2016: 2 · 2015: 5 · 2014: 4 · 2013: 9 · 2012: 7
- FWCI
- 2.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Rockefeller Foundation
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-37867)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- gene conversion, unequal crossover, CYP21, 21-hydroxylase, congenital adrenal hyperplasia, meiotic recombination, mitotic recombination, de novo deletion, sperm DNA, leukocyte DNA, intron 2, exon 3
- MeSH terms
- Adrenal Hyperplasia, Congenital, Adult, Base Sequence, Crossing Over, Genetic, Gene Conversion, Humans, Hydrocortisone, Leukocytes, Male, Meiosis, Mitosis, Molecular Sequence Data, Pseudogenes, Spermatozoa, Steroid 21-Hydroxylase, Polymerase Chain Reaction, Sequence Deletion
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