ArticleProceedings of the National Academy of Sciences of the United States of America2013
Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Who cites it
58 citing papers in PubMed, 124 citations in OpenAlex.
- Functional analysis of 11 CYP21A2 variants reveals greater loss of enzyme activity in cis variants and improves genotype-phenotype correlation in 21-hydroxylase deficiency.Journal of endocrinological investigation · 2026Article
- Case Report: Compound heterozygous mutation comprising p.Pro31Leu and exons 1-3 ins/del variants inFrontiers in pediatrics · 2026Article
- Neonatal Screening for Congenital Adrenal Hyperplasia in Guangzhou: 7 Years of Experience.International journal of neonatal screening · 2025Article
- Clinical and molecular characteristics of simple virilizing congenital adrenal hyperplasia due to 21-hydroxylase deficiency: insight from a tertiary pediatric center in Vietnam.Annals of pediatric endocrinology & metabolism · 2025Article
- Transcript Patterns of BovineGenes · 2025Article
- Longitudinal 12-Month Follow-Up of a Male Infant withAJP reports · 2025Article
- Optimized Homologous Sequence Alignment for the Identification of CYP21A2 Variants in 21-Hydroxylase Deficiency Using Next-Generation Sequencing Technology.Risk management and healthcare policy · 2025Article
- Comprehensive characterization of 21-hydroxylase deficiency in a Chinese pediatric cohort: phenotype, steroid profiles and genetics.Frontiers in endocrinology · 2025Article
- Long-read sequencing transforms the diagnosis of congenital adrenal hyperplasia: resolving pseudogene interference and structural variations.Frontiers in pediatrics · 2025Article
- Genetics of 21-OH Deficiency and Genotype-Phenotype Correlation: Experience of the Hellenic National Referral Center.Current issues in molecular biology · 2024Article
- Design and synthesis of phosphoryl-substituted steroidal pyridazines (Pho-STPYRs) as potent estrogen receptor alpha inhibitors: targeted treatment of hormone-dependent breast cancer cells.RSC medicinal chemistry · 2024Article
- A Humanized and Viable Animal Model for Congenital Adrenal Hyperplasia-International journal of molecular sciences · 2024Article
- Approaching fertility in congenital adrenal hyperplasia: exploring P30L mutation-induced 21-hydroxylase deficiency with a presentation between non-classical and simple virilizing phenotypes. A case report.Medicine and pharmacy reports · 2024Article
- Article
- The "outsized" role of the I-helix kink in human Cytochrome P450s.Clinical and translational medicine · 2023Article
- Article
- Evolution of genes involved in the unusual genitals of the bear macaque,Ecology and evolution · 2022Article
- Congenital adrenal hyperplasia with homozygous and heterozygous mutations: a rare family case report.BMC endocrine disorders · 2022Article
- Innate immune genes of the chicken MHC and related regions.Immunogenetics · 2022Review
- Congenital Adrenal Hyperplasia-Current Insights in Pathophysiology, Diagnostics, and Management.Endocrine reviews · 2022Review
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 3 countries.
Funding
Abstract
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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