Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia
Open accessAbstract
Mutations in the cytochrome p450 (CYP)21A2 gene, which encodes the enzyme steroid 21-hydroxylase, cause the majority of cases in congenital adrenal hyperplasia, an autosomal recessive disorder. To date, more than 100 CYP21A2 mutations have been reported. These mutations can be associated either with severe salt-wasting or simple virilizing phenotypes or with milder nonclassical phenotypes. Not all CYP21A2 mutations have, however, been characterized biochemically, and the clinical consequences of these mutations remain unknown. Using the crystal structure of its bovine homolog as a template, we have constructed a humanized model of CYP21A2 to provide comprehensive structural explanations for the clinical manifestations caused by each of the known disease-causing missense mutations in CYP21A2. Mutations that affect membrane anchoring, disrupt heme and/or substrate binding, or impair stability of CYP21A2 cause complete loss of function and salt-wasting disease. In contrast, mutations altering the transmembrane region or conserved hydrophobic patches cause up to a 98% reduction in enzyme activity and simple virilizing disease. Mild nonclassical disease can result from interference in oxidoreductase interactions, salt-bridge and hydrogen-bonding networks, and nonconserved hydrophobic clusters. A simple in silico evaluation of previously uncharacterized gene mutations could, thus, potentially help predict the often diverse phenotypes of a monogenic disorder.
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Girls and women with more severe CYP21A2 genotypes appear to have an increased risk for psychiatric conditions.
“However, girls and women with more severe CYP21A2 genotypes appear to have an increased risk for psychiatric conditions (228)”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [228]
The Abstract describes how CYP21A2 mutations relate to the severity and physical manifestations of congenital adrenal hyperplasia, and the Discussion describes modeling clinical severity. Neither addresses psychiatric risk in girls or women; searches for psychiatric conditions and mental-health terms found no relevant passage in our copy. (LLM, conf=0.74)
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- Authors
- Haider, S., Islam, B., D’Atri, V., Sgobba, M., Poojari, C., Sun, L., Yuen, T., Zaidi, M., & New, M. I.
- Affiliations
- Queen's University Belfast (GB)
- Forschungszentrum Jülich (DE)
- Departments of cMedicine and
- Icahn School of Medicine at Mount Sinai (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-01-28
- Volume
- 110
- Issue
- 7
- Pages
- 2605-2610
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3574933
- OpenAlex
- W2001330488
- Cited by
- 127
- References
- 42
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 8 · 2023: 7 · 2022: 8 · 2021: 10 · 2020: 7 · 2019: 12 · 2018: 9 · 2017: 11 · 2016: 13 · 2015: 10 · 2014: 12 · 2013: 7
- FWCI
- 6.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (Queen's University Belfast) (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Institute on Aging (R01AG040132)
- 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 › Molecular Biology › Protein Structure and Dynamics
- Keywords
- CYP21A2, congenital adrenal hyperplasia, 21-hydroxylase, missense mutations, salt-wasting phenotype, non-classical congenital adrenal hyperplasia, protein structure modeling, heme binding, substrate binding, transmembrane domain, hydrophobic clusters, genotype-phenotype prediction
- MeSH terms
- Adrenal Hyperplasia, Congenital, Animals, Cattle, Cell Membrane, Heme, Humans, Hydrogen Bonding, Models, Molecular, Phenotype, Protein Binding, Protein Conformation, Steroid 21-Hydroxylase, Computational Biology, Mutation, Missense, Molecular Dynamics Simulation
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