Deletion Hybrid Genes, due to Unequal Crossing Over between CYP11B1(11β-Hydroxylase) and CYP11B2(Aldosterone Synthase) Cause Steroid 11β-Hydroxylase Deficiency and Congenital Adrenal Hyperplasia1
Abstract
Chromosomal rearrangements are natural experiments that can provide unique insights into in vivo regulation of genes and physiological systems. We have studied a patient with congenital adrenal hyperplasia and steroid 11beta-hydroxylase deficiency who was homozygous for a deletion of the CYP11B1 and CYP11B2 genes normally required for cortisol and aldosterone synthesis, respectively. The genes were deleted by unequal recombination between the tandemly arranged CYP11B genes during a previous meiosis, leaving a single hybrid gene consisting of the promoter and exons 1-6 of CYP11B2 and exons 7-9 of CYP11B1. The hybrid gene also carried an I339T mutation formed by intracodon recombination at the chromosomal breakpoint. The mutant complementary DNA corresponding to this gene was expressed in COS-1 cells and was found to have relatively unimpaired 11beta-hydroxylase and aldosterone synthase activities. Apparently the 11beta-hydroxylase deficiency and the adrenal hyperplasia are due to the lack of expression of this gene in the adrenal zona fasciculata/reticularis resulting from replacement of the CYP11B1 promoter and regulatory sequences by those of CYP11B2.
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Crossover has been described in intron 2, intron 3, and exon 4, and the corresponding deleted allele, causing 11-hydroxylase deficiency, has been described.
“Crossover has been described in intron 2, intron 3, and exon 4 (491), and the corresponding deleted allele, causing 11-hydroxylase deficiency, has been described (493).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [493]
Cites
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Cloning and expression of a cDNA for human cytochrome P-450aldo as related to primary aldosteronism
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The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders
Miller, W. L., & Auchus, R. J. (2011) · Endocrine Reviews · doi:10.1210/er.2010-0013 · Cited by 2,458 · see citing works
Molecular diagnosis of steroid 21-hydroxylase deficiency: A practical approach
Arriba, M., & Ezquieta, B. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.834549 · Cited by 30 · see citing works
Inherited Disorders of Renal Salt Homeostasis
Scholl, U. I., & Lifton, R. P. (2013) · Seldin and Giebisch's The Kidney · doi:10.1016/b978-0-12-381462-3.00036-7 · Cited by 10 · see citing works
- Authors
- Portrat, S., Mulatero, P., Curnow, K. M., Chaussain, J.-L., Morel, Y., & Pascoe, L.
- Affiliations
- University of Turin (IT)
- Hôpital Saint-Vincent-de-Paul (FR)
- Inserm (FR)
- Fondation Jean Dausset-CEPH (FR)
- Corresponding author
- Pascoe, Leigh
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2001-07
- Volume
- 86
- Issue
- 7
- Pages
- 3197-3201
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2136070934
- Cited by
- 46
- References
- 3
- Citations by year
- 2024: 4 · 2023: 3 · 2022: 3 · 2018: 3 · 2017: 2 · 2016: 1 · 2015: 3 · 2014: 1 · 2013: 2 · 2012: 1
- FWCI
- 1.85
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Keywords
- congenital adrenal hyperplasia, 11beta-hydroxylase deficiency, CYP11B1, CYP11B2, unequal crossover, chromosomal rearrangements, hybrid genes, tandem gene arrangement, promoter replacement, adrenal zona fasciculata, aldosterone synthase, cortisol production, gene expression regulation
- MeSH terms
- Adrenal Hyperplasia, Congenital, Aldosterone, Androstenedione, Animals, Child, Preschool, Cortodoxone, Crossing Over, Genetic, Exons, Homozygote, Humans, Male, Promoter Regions, Genetic, Puberty, Precocious, Renin, Steroid 11-beta-Hydroxylase, Transfection, Blotting, Southern, Gene Expression, Polymerase Chain Reaction, Gene Deletion, Cyproterone Acetate, DNA, Complementary, Cytochrome P-450 CYP11B2, COS Cells
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