Substitutions in the CYP21A2 promoter explain the simple‐virilizing form of 21‐hydroxylase deficiency in patients harbouring a P30L mutation

Araujo, Rogério S.; Billerbeck, Ana Elisa C.; Madureira, Guiomar; Mendonca, Berenice B.; Bachega, Tânia A. S. S.

doi:10.1111/j.1365-2265.2005.02184.x

Cited by 42Sexual Differentiation and DisordersAdrenal Hormones and DisordersMetabolism and Genetic Disorders

Substitutions in the CYP21A2 promoter explain the simple‐virilizing form of 21‐hydroxylase deficiency in patients harbouring a P30L mutation

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Araujo, Rogério S., Billerbeck, Ana Elisa C., Madureira, Guiomar, Mendonca, Berenice B., Bachega, Tânia A. S. S.·2005·Clinical Endocrinology

DOI 10.1111/j.1365-2265.2005.02184.x

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Abstract

The classical and nonclassical phenotypes of 21-hydroxylase deficiency represent a continuous spectrum of the impairment of 21-hydroxylase activity due to mutations between the CYP21A2 gene. These mutations occur mainly by microconversion in the homologous nonfunctional CYP21A1P gene. The P30L mutation is associated with the nonclassical form, and it reduces the activity to 30-40% of the normal enzyme. We have described three female patients exhibiting a simple virilizing phenotype and bearing the P30L mutation in compound heterozygosis with a severe mutation. To identify additional mutations causing this phenotype, the promoter region was sequenced and four mutations were identified: -126C --> T, -113G --> A, -110T --> C and -103 A --> G. These substitutions are normally present in the promoter region of the pseudogene and in vitro studies demonstrated that they reduced the transcriptional activity fivefold. They might have been converted to the CYP21A2 promoter together with the P30L mutation in these patients. Therefore, these substitutions in synergism with the P30L mutation might decrease the enzyme activity resulting in a more severe phenotype, and a DNA sequence of -167 bases of the CYP21A2 gene should be performed in patients with 21-hydroxylase deficiency in whom the phenotype is more severe than predicted by the genotype.

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In cultured mouse Y-1 or human H295 adrenocortical cells, the 5' flanking region of human CYP21A2 drives basal expression of reporter constructs at levels 2.5-8 times higher than the corresponding region of CYP21A1P.
“In cultured mouse Y-1 or human H295 adrenocortical cells, the 5' flanking region of human CYP21A2 drives basal expression of reporter constructs at levels 2.5-8 times higher than the corresponding region of CYP21A1P (176-178).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [178]

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“…upstream regulatory regions (such as c.-126C>T, c.-113G>A, c.-110T>C, and c.-103A>G), reduce transcriptional output and can modify the phenotypic impact of missense variants like p.(Pro31Leu), shifting expected NC/SV presentations toward increased androgen excess as promoter activity declines (78).”
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Genotype and Phenotype of 21-Hydroxylase Deficiency: A Single Center Experience from Western India
Karlekar, M. P., Barnabas, R., Sarathi, V., Lila, A. R., Arya, S., Hegishte, S. C., Bhandare, V. V., Memon, S. S., Patil, V. A., Bandgar, T., et al. (2024) · Indian Pediatrics · doi:10.1007/s13312-024-3296-8 · Cited by 1 · see citing works
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Menabò, S. (2021) · L Endocrinologo · doi:10.1007/s40619-021-00838-z · Cited by 1 · see citing works
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Variations in the promoter of CYP21A2 gene identified in a Chinese patient with simple virilizing form of 21‐hydroxylase deficiency
Zhang, H., Yang, J., Zhang, M., Zhang, W., Liu, J., Wang, W., Ning, G., & Li, X. (2008) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2008.03356.x · Cited by 18 · see citing works
Microconversion betweenCYP21A2andCYP21A1PPromoter Regions Causes the Nonclassical Form of 21-Hydroxylase Deficiency
Araújo, R. S., Mendonca, B. B., Barbosa, A. S., Lin, C. J., Marcondes, J. A. M., Billerbeck, A. E. C., & Bachega, T. A. S. S. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-2163 · Cited by 70 · see citing works
Self-citation
A Mutation (Pro-30 to Leu) inCYP21 Represents a Potential Nonclassic Steroid 21-Hydroxylase Deficiency Allele
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The underlying cause of the simple virilizing phenotype in patients with 21-hydroxylase deficiency harboring P31L variant
Zhao, Z., Gao, Y., Lü, L., Tong, A., Chen, S., Zhang, W., Zhang, X., Sun, B., Wu, X., Mao, J., et al. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1015773 · Cited by 6 · see citing works
Phenotype-genotype correlations of 13 rare CYP21A2 mutations detected in 46 patients affected with 21-hydroxylase deficiency and in one carrier
Tardy, V., Menassa, R., Sulmont, V., Lienhardt-Roussie, A., Lecointre, C., Brauner, R., David, M., & Morel, Y. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-1202 · Cited by 73 · see citing works

Authors: Araujo, R. S., Billerbeck, A. E. C., Madureira, G., Mendonca, B. B., & Bachega, T. A. S. S.
Affiliations: Universidade de São Paulo (BR)
Corresponding author: Bachega, Tânia A. S. S.
ORCID: Mendonca, Berenice B.
Bachega, Tânia A. S. S.
Venue: Clinical Endocrinology
Publisher: Wiley
Published: 2005-01-13
Volume: 62
Issue: 2
Pages: 132-136
ISSN: 0300-0664 (ISSN-L)
1365-2265
DOI: 10.1111/j.1365-2265.2005.02184.x
OpenAlex: W1995548505
Cited by: 42
References: 36
Citations by year: 2026: 2 · 2025: 6 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 4 · 2020: 4 · 2019: 2 · 2017: 2 · 2016: 1 · 2015: 2 · 2014: 1 · 2012: 3
FWCI: 0.50
Type: journal article
Language: en
Open access: green
www.blackwell-synergy.com
Licence: other-oa
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Clinical Endocrinology (publishedVersion)
LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, other-oa)
PubMed (publishedVersion)
Funders: Faculdade de Medicina da Universidade de São Paulo
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: 21-hydroxylase deficiency, promoter mutations, compound heterozygosity, transcriptional activity, enzyme activity, genotype-phenotype correlation, female patients
MeSH terms: Adolescent, Adrenal Hyperplasia, Congenital, Child, Child, Preschool, DNA Mutational Analysis, Female, Genotype, Humans, Mutation, Phenotype, Promoter Regions, Genetic, Steroid 21-Hydroxylase

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Substitutions in the CYP21A2 promoter explain the simple‐virilizing form of 21‐hydroxylase deficiency in patients harbouring a P30L mutation

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