Four novel missense mutations in the CYP21A2 gene detected in Russian patients suffering from the classical form of congenital adrenal hyperplasia: identification, functional characterization, and structural analysis
Abstract
Context: Congenital adrenal hyperplasia is a group of autosomal recessive inherited disorders of steroidogenesis. The most frequent cause is the deficiency of steroid 21-hydroxylase (CYP21) due to mutations in the CYP21A2 gene. Objective: We analyzed the functional and structural consequences of the four CYP21A2 missense mutations (C169R, G178R, W302R, and R426C) to prove their clinical relevance and study their impact on CYP21 function. Results: Analyzing the mutations in vitro revealed an almost absent or negligible CYP21 activity for the conversion of 17-hydroxyprogesterone to 11-deoxycortisol and progesterone to deoxycorticosterone. Protein translation and intracellular localization were not affected by the mutants, as could be demonstrated by Western blotting and immunofluorescence studies. Analysis of these mutants in a three-dimensional model structure of the CYP21 protein explained the observed in vitro effects because all the mutations severely interfere either directly or indirectly with important structures of the 21-hydroxylase protein. Conclusion: The in vitro expression analysis of residual enzyme function is a complementary method to genotyping and an important tool for improving the understanding of the clinical phenotype of 21-hydroxylase deficiency. This forms the foundation for accurate clinical and genetic counseling and for prenatal diagnosis and treatment. Moreover, this report demonstrates that the combination of in vitro enzyme analysis and molecular modeling can yield novel insights into CYP450 structure-functional relationships.
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Other rare alleles, which are true mutations rather than gene conversions, have been described in single individuals.
“Other rare alleles, which are true mutations rather than gene conversions, have been described in single individuals (436 -440).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [440]
Each missense mutation appears to occur in a functional domain of P450c21.
“Each missense mutation appears to occur in a functional domain of P450c21 (440).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [440]
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Self-citation
- Authors
- Grischuk, Y., Rubtsov, P., Riepe, F. G., Grötzinger, J., Beljelarskaia, S., Prassolov, V., Kalintchenko, N., Semitcheva, T., Peterkova, V., Tiulpakov, A., Sippell, W. G., & Krone, N.
- Affiliations
- Engelhardt Institute of Molecular Biology (RU)
- Engelhardt Institute of Molecular Biology (Y.G., P.R., S.B., V.Pr.), Russian Academy of Sciences, Moscow 119991, Russian Federation
- Christian-Albrechts-Universität zu Kiel (DE)
- Biochemisches Institut (J.G.), Christian-Albrechts-Universität zu Kiel, D-24098 Kiel, Germany
- Endocrinology Research Center (RU)
- Corresponding author
- Krone, Nils
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2006-12-01
- Volume
- 91
- Issue
- 12
- Pages
- 4976-4980
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W1978578326
- Semantic Scholar
- d140ce1168eb5ec2e1a0cf819c0f3f7f67150d96
- Cited by
- 33
- References
- 20
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 1 · 2020: 1 · 2019: 1 · 2017: 3 · 2013: 4
- FWCI
- 1.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- 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
- congenital adrenal hyperplasia, CYP21A2, 21-hydroxylase deficiency, missense mutations, 21-hydroxylase, enzyme activity, protein structure-function relationship, molecular modeling, Russian patients, genetic counseling
- MeSH terms
- Adolescent, Adrenal Hyperplasia, Congenital, Amino Acid Sequence, Animals, Chlorocebus aethiops, Child, DNA Mutational Analysis, Female, Humans, Infant, Male, Models, Molecular, Molecular Sequence Data, Protein Conformation, Puberty, Precocious, Russia, Disorders of Sex Development, Steroid 21-Hydroxylase, Structure-Activity Relationship, Sequence Homology, Amino Acid, COS Cells, Mutation, Missense
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