Microconversion between CYP21A2 and CYP21A1P Promoter Regions Causes the Nonclassical Form of 21-Hydroxylase Deficiency

Araújo, Rogério S.; Mendonca, Berenice B.; Barbosa, Ângela S.; Lin, Chin J.; Marcondes, José A. M.; Billerbeck, Ana Elisa C.; Bachega, Tânia A. S. S.

doi:10.1210/jc.2006-2163

Cited by 70Sexual Differentiation and DisordersAdrenal Hormones and DisordersMetabolism and Genetic Disorders

Microconversion between CYP21A2 and CYP21A1P Promoter Regions Causes the Nonclassical Form of 21-Hydroxylase Deficiency

Araújo, Rogério S., Mendonca, Berenice B., Barbosa, Ângela S., Lin, Chin J., Marcondes, José A. M., Billerbeck, Ana Elisa C., Bachega, Tânia A. S. S.·2007·The Journal of Clinical Endocrinology & Metabolism

DOI 10.1210/jc.2006-2163

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Abstract

CONTEXT: Most mutations causing 21-hydroxylase deficiency originate from microconversions between CYP21 pseudogenes and active genes. However, around 20% of the alleles in the nonclassical form (NC-21OHD) remain without identified mutations, suggesting the involvement of regulatory regions. The pseudogene promoter is 80% less active than the CYP21A2 due to the presence of -126C>T, -113G>A, -110T>C, and -103A>G mutations. Additionally, mutations in the steroidogenic factor-1 binding sites of the CYP21 distal regulatory region, located at 4676 bases upstream from the cap site of the CYP21A2 gene, decrease its transcription to 35%. OBJECTIVE: The objective of the study was to investigate the CYP21A2 promoter/regulatory regions in NC-21OHD patients with undetermined genotype. SUBJECTS: The study included 17 NC-21OHD patients and 50 controls. METHODS: Promoter/regulatory regions were sequenced from peripheral leukocytes' genomic DNA. The identified substitutions were evaluated through EMSA using -132/-97 wild-type and mutant probes and nuclear extracts from NCI-H295A cells. Transcriptional activity studies were performed with wild-type and mutant constructions transfected in NCI-H295A cells. RESULTS: No mutations were identified in the distal regulatory regions. The -126C>T, -113G>A, -110T>C promoter mutations were found in compound heterozygosity with the V281L mutation in one patient and the -126C>T mutation in compound heterozygosity with the I2 splice in another. The -126T mutation decreases the transcriptional activity to 52%, compatible with the patient's nonclassical phenotype. EMSA demonstrated that the -132/-121 region is important for the DNA interaction with the specificity protein-1 transcription factor. CONCLUSION: Microconversions between CYP21A2 and CYP21A1P promoters could be involved in the nonclassical phenotype. Therefore CYP21A2 promoter analysis should be included in genetic studies of 21OHD.

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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 [177]

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Two novel CYP21A2 missense mutations in Italian patients with 21‐hydroxylase deficiency: Identification and functional characterisation
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Misregulation effect of a novel allelic variant in the Z promoter region found in cis with the CYP21A2 p.P482S mutation: implications for 21-hydroxylase deficiency
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[Correlation between variants of CYP21A2 gene promoter region and nonclassical 21-hydroxylase deficiency].
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Authors: 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.
Affiliations: Unidade de Endocrinologia do Desenvolvimento e Laboratorio de Hormonios e Genetica Molecular (R.S.A., B.B.M., C.J.L., J.A.M.M., A.E.C.B., T.A.S.S.B.), LIM/42, Disciplina de Endocrinologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, SP 05403-900, Brazil
Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (BR)
Centro de Biotecnologia (A.S.B.), Instituto Butantan, 05504-900 Sao Paulo, SP, Brazil
ORCID: Mendonca, Berenice B.
Venue: The Journal of Clinical Endocrinology & Metabolism
Publisher: The Endocrine Society
Published: 2007-10-01
Volume: 92
Issue: 10
Pages: 4028-4034
ISSN: 0021-972X (ISSN-L)
1945-7197
DOI: 10.1210/jc.2006-2163
OpenAlex: W2034334001
Cited by: 70
References: 50
Citations by year: 2026: 6 · 2025: 5 · 2024: 2 · 2023: 5 · 2022: 6 · 2021: 9 · 2020: 4 · 2019: 2 · 2018: 1 · 2017: 4 · 2016: 2 · 2015: 2 · 2014: 3 · 2013: 3 · 2012: 3
FWCI: 1.32
Type: journal article
Language: en
Open access: closed
Locations: The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
PubMed (publishedVersion)
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, Sp1, transcriptional activity, steroidogenesis
MeSH terms: Adolescent, Adrenal Hyperplasia, Congenital, Adult, Base Sequence, Child, Female, Humans, Introns, Male, Phenotype, Promoter Regions, Genetic, Pseudogenes, Steroid 21-Hydroxylase, DNA Probes, Point Mutation, Electrophoretic Mobility Shift Assay

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Microconversion between CYP21A2 and CYP21A1P Promoter Regions Causes the Nonclassical Form of 21-Hydroxylase Deficiency

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