Functional characterization of three CYP21A2 sequence variants (p.A265V, p.W302S, p.D322G) employing a yeast co-expression system: Functional Characterization of CYP21A2 Variants
Open accessAbstract
Congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase (CYP21A2) deficiency is the commonest inborn error in steroid hormone biosynthesis. Functional in vitro assessment of mutant activity generally correlates well with clinical phenotype and therefore has contributed greatly to phenotype prediction in this CAH variant. Three CYP21A2 sequence variants (g.1641C>T, p.A265V; g.1752G>C, p.W302S; and g.2012A>G, p.D322G) identified in patients with non-classic and simple virilizing CAH were characterized using a yeast co-expression system and a computational three-dimensional CYP21A2 model. Computational analysis of the mutants in the three-dimensional structural model predicted no relevant effect of p.A265V, while p.W302S and p.D322G were predicted to impact significantly on enzyme function. Consistent with these findings, in vitro mutant analysis revealed enzyme activity similar to wild-type for p.A265V, whereas p.W302S and p.D322G exerted activities compatible with simple virilizing and non-classical CAH, respectively. The results indicate that p.A265V is an allelic variant rather than a disease-causing amino acid change, whilst p.W302S and p.D322G could be confirmed as functionally relevant mutations. These findings emphasize the value of in vitro functional analysis of sequence variations in predicting genotype-phenotype correlations and disease severity.
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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 [439]
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The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders
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- Authors
- Bleicken, C., Loidi, L., Dhir, V., Parajes, S., Quinteiro, C., Dominguez, F., Grötzinger, J., Sippell, W. G., Riepe, F. G., Arlt, W., & Krone, N.
- Affiliations
- University of Würzburg (DE)
- Fundación Pública Galega de Medicina Xenómica (ES)
- University of Birmingham (GB)
- Christian-Albrechts-Universität zu Kiel (DE)
- University Hospital Schleswig-Holstein (DE)
- Corresponding author
- Krone, Nils
- Venue
- Human Mutation
- Publisher
- Hindawi Limited
- Published
- 2008-12-04
- Volume
- 30
- Issue
- 2
- Pages
- E443-E450
- ISSN
- 1059-7794 (ISSN-L)
- OpenAlex
- W2015778532
- Cited by
- 15
- References
- 22
- Citations by year
- 2020: 1 · 2017: 2 · 2015: 1 · 2014: 3 · 2013: 2 · 2012: 2
- FWCI
- 0.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Mutation (publishedVersion)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- Wellcome Trust (Clinician Scientist Fellowship to NK) (GR079865MA)
- Medical Research Council UK (Senior Clinical Fellowship to WA) (G116/172)
- Deutsche Forschungsgemeinschaft to WA (AL203-9)
- Deutsche Forschungsgemeinschaft to NK (KR 3363/1-1)
- 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
- CYP21A2, congenital adrenal hyperplasia, 21-hydroxylase deficiency, genetic variants, enzyme activity, genotype-phenotype correlation, simple virilizing CAH, 3D structural model
- MeSH terms
- Adolescent, Child, Female, Humans, Kinetics, Models, Molecular, Mutation, Saccharomyces cerevisiae, Steroid 21-Hydroxylase, Transcription, Genetic, Protein Biosynthesis, Protein Structure, Secondary, Mutant Proteins
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