Skip to main content

Advertisement

SpringerLink
Log in

Detection of a novel severe mutation affecting the CYP21A2 gene in a Chilean male with salt wasting congenital adrenal hyperplasia

  • Endocrine Genetics/Epigenetics
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Purpose

21-hydroxylase deficiency (21-OHD) is a congenital adrenal disease with more than 200 mutations published to date. The aim of this report is to describe a severe novel mutation of the CYP21A2 gene.

Method

We describe a case of a 39-year-old male diagnosed with a salt wasting congenital adrenal hyperplasia (SWCAH) due to 21-OHD. The genetic testing was done using a combination of three methods (PCR XL, SALSA-MLPA, and bidirectional sequencing) and finally an in silico analysis.

Results

The genetic testing demonstrated three severe mutations of the CYP21A2 gene (p.Gln318*; c.290-13C>G; and p.Trp86*), being the last one a novel mutation not previously reported. The in silico modeling of the p.Trp86* (c.258G>A) showed a truncated CYP21A2 protein that loses all the main structural features required for activity, such as the HEM binding domain and the hormone binding site.

Conclusion

We present an adult man with an SWCAH due to 21-OHD who carried three severe mutations of the CYP21A2 gene, one of them, p.Trp86* (c.258G>A) has not been previously described.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. D. El-Maouche, W. Arlt, D.P. Merke, Congenital adrenal hyperplasia. Lancet 390, 2194–2210 (2017)

    Article  CAS  Google Scholar 

  2. P.W. Speiser, W. Arlt, R.J. Auchus, L.S. Baskin, G.S. Conway, D.P. Merke et al. Congenital adrenal hyperplasia due to steroid 21-Hydroxylase deficiency: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 103, 4043–4088 (2018)

    Article  Google Scholar 

  3. F. Hannah-Shmouni, W. Chen, D.P. Merke, Genetics of congenital adrenal hyperplasia. Endocrinol. Metab. Clin. North Am. 46, 435–458 (2017)

    Article  Google Scholar 

  4. B.L. Therrell, S.A. Berenbaum, V. Manter-Kapanke, J. Simmank, K. Korman, L. Prentice et al. Results of screening 1.9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia. Pediatrics 101, 583–590 (1998)

    Article  Google Scholar 

  5. P.W. Speiser, R. Azziz, L.S. Baskin, L. Ghizzoni, T.W. Hensle, D.P. Merke et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 95, 4133–4160 (2010)

    Article  CAS  Google Scholar 

  6. P.W. Speiser, B. Dupont, P. Rubinstein, A. Piazza, A. Kastelan, M.I. New, High frequency of nonclassical steroid 21-hydroxylase deficiency. Am. J. Hum. Genet. 37, 650–667 (1985)

    CAS  PubMed  PubMed Central  Google Scholar 

  7. D.W. Nebert, D.R. Nelson, M.J. Coon, R.W. Estabrook, R. Feyereisen, Y. Fujii-Kuriyama et al. The P450 superfamily: update on new sequences, gene mapping, and recommended nomenclature. DNA Cell Biol. 10, 1–14 (1991)

    Article  CAS  Google Scholar 

  8. P.W. Speiser, P.C. White, Congenital adrenal hyperplasia. N. Engl. J. Med. 349, 776–788 (2003)

    Article  CAS  Google Scholar 

  9. Z. Vrzalová, Z. Hrubá, E.S. Hrabincová, S. Vrábelová, F. Votava, S. Koloušková et al. Chimeric CYP21A1P/CYP21A2 genes identified in Czech patients with congenital adrenal hyperplasia. Eur. J. Med. Genet. 54, 112–117 (2011)

    Article  Google Scholar 

  10. P.W. Speiser, J. Dupont, D. Zhu, J. Serrat, M. Buegeleisen, M.T. Tusie-Luna et al. Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J. Clin. Investig. 90, 584–595 (1992)

    Article  CAS  Google Scholar 

  11. M.I. New, M. Abraham, B. Gonzalez, M. Dumic, M. Razzaghy-Azar, D. Chitayat et al. Genotype–phenotype correlation in 1507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Proc. Natl. Acad. Sci. Usa. 110, 2611–2616 (2013)

    Article  CAS  Google Scholar 

  12. P. Concolino, A. Costella, Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency: a comprehensive focus on 233 pathogenic variants of CYP21A2 gene. Mol. Diagn. Ther. 22, 261–280 (2018)

    Article  CAS  Google Scholar 

  13. D. Keen-Kim, J.B. Redman, R.U. Alanes, M.M. Eachus, R.C. Wilson, M.I. New et al. Validation and clinical application of a locus-specific polymerase chain reaction- and minisequencing-based assay for congenital adrenal hyperplasia (21-hydroxylase deficiency). J. Mol. Diagn. 7, 236–246 (2005)

    Article  CAS  Google Scholar 

  14. A. Wedell, E.M. Ritzen, B. Haglund-Stengler, H. Luthman, Steroid 21-hydroxylase deficiency: three additional mutated alleles and establishment of phenotype-genotype relationships of common mutations. Proc. Natl Acad. Sci. USA. 89, 7232–7236 (1992)

    Article  CAS  Google Scholar 

  15. A. Sali, T.L. Blundell, Comparative protein modelling by satisfaction of spatial restraints. J. Mol. Biol. 234, 779–815 (1993)

    Article  CAS  Google Scholar 

  16. P.S. Pallan, C. Wang, L. Lei, F.K. Yoshimoto, R.J. Auchus, M.R. Waterman et al. Human cytochrome P450 21A2, the major steroid 21-Hydroxylase: structure of the enzyme, progesterone substrate and rate-limiting C-H bond cleavage. J. Biol. Chem. 290, 13128–13143 (2015)

    Article  CAS  Google Scholar 

  17. Q.S. Zhao, S. Modi, G. Smith, M. Paine, P. McDonagh, P.D. Wolf, et al., Crystal structure of the FMN-binding domain of human cytochrome P450 reductase at 1.93 Å resolution. Protein Sci. 8, 298–306 (1999)

    Article  CAS  Google Scholar 

  18. D. Kozakov, D.R. Hall, B. Xia, K.A. Porter, D. Padhorny, C. Yueh et al. The ClusPro web server for protein–protein docking. Nat. Protoc. 12, 255–278 (2017)

    Article  CAS  Google Scholar 

  19. S.R. Comeau, D.W. Gatchell, S. Vajda, C.J. Camacho, ClusPro: an automated docking and discrimination method for the prediction of protein complexes. Bioinformatics 20, 45–50 (2004)

    Article  CAS  Google Scholar 

  20. B.R. Brooks, C.L. Brooks 3rd, A.D. Mackerell Jr, L. Nilsson, R.J. Petrella, B. Roux et al. CHARMM: the biomolecular simulation program. J. Comput. Chem. 30, 1545–1614 (2009)

    Article  CAS  Google Scholar 

  21. J.M. Schwarz, C. Rödelsperger, M. Schuelke, D. Seelow, MutationTaster evaluates disease-causing potential of sequence alterations. Nat. Methods 7, 575–576 (2010)

    Article  CAS  Google Scholar 

  22. Y. Choi, A.P. Chan, PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics 31, 2745–2747 (2015)

    Article  CAS  Google Scholar 

  23. M. Mort, T. Sterne-Weiler, B. Li, E.V. Ball, D.N. Cooper, P. Radivojac et al. MutPred Splice: machine learning-based prediction of exonic variants that disrupt splicing. Genome Biol. 15, R19 (2014)

    Article  Google Scholar 

  24. I.A. Adzhubei, S. Schmidt, L. Peshkin, V.E. Ramensky, A. Gerasimova, P. Bork et al. A method and server for predicting damaging missense mutations. Nat. Methods 7, 248–249 (2010)

    Article  CAS  Google Scholar 

  25. C.E. Fardella, H. Poggi, P. Pineda, J. Soto, I. Torrealba, A. Cattani et al. Salt-wasting congenital adrenal hyperplasia: detection of mutations in CYP21B gene in a Chilean population. J. Clin. Endocrinol. Metab. 83, 3357–3360 (1998)

    CAS  PubMed  Google Scholar 

  26. E. Mornet, J.F. Gibrat, A 3D model of human P450c21: study of the putative effects of steroid 21-hydroxylase gene mutations. Hum. Genet. 106, 330–339 (2000)

    Article  CAS  Google Scholar 

  27. M. Janner, A.V. Pandey, P.E. Mullis, C.E. Flück, J. Marco, V.P. Amit, E.M. Primus, E.F.C. Christa, Clinical and biochemical description of a novel CYP21A2 gene mutation 962_963insA using a new 3D model for the P450c21 protein. Eur. J. Endocrinol. 155, 143–151 (2006)

    Article  CAS  Google Scholar 

  28. S. Haider, B. Islam, V. D’Atri, M. Sgobba, C. Poojari, L. Sun et al. Structure–phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia. Proc. Natl Acad. Sci. USA 110, 2605–2610 (2013)

    Article  CAS  Google Scholar 

  29. C. Wang, P.S. Pallan, W. Zhang, L. Lei, F.K. Yoshimoto, M.R. Waterman, Functional analysis of human cytochrome P450 21A2 variants involved in congenital adrenal hyperplasia. J. Biol. Chem. 292, 10767–10778 (2017)

    Article  CAS  Google Scholar 

  30. P.S. Pallan, L. Lei, C. Wang, M.R. Waterman, F.P. Guengerich, M. Egli, Research resource: correlating human cytochrome P450 21A2 crystal structure and phenotypes of mutations in congenital adrenal hyperplasia. Mol. Endocrinol. 29, 1375–1384 (2015)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Catalina Tobar, MD for presenting this case report to the national annual meeting of endocrinology in Chile.

Funding

Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT) Project Number 1160695, IMII P09/016-F.

Author information

Authors and Affiliations

  1. Departamento de Endocrinología and Centro Traslacional en Endocrinología (CETREN), Facultad de Medicina, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, Piso 4, Santiago Centro, 8330077, Santiago, Chile

    Eugenio Arteaga, Felipe Valenzuela, Alejandra Martinez, Rene Baudrand, Cristian Carvajal & Carlos E. Fardella

  2. Facultad de Medicina y Ciencia, Universidad San Sebastián, Campus Los Leones, Lota 2465, Providencia, 7510157, Santiago, Chile

    Carlos F. Lagos

  3. Departamento de Laboratorios Clínicos, Facultad de Medicina, Pontificia Universidad Católica de Chile, Av. Vicuña Mackenna 4686, Piso 3, Macul, 7820436, Santiago, Chile

    Marcela Lagos

  4. Instituto Milenio en Inmunología e Inmunoterapia IMII, Portugal 49, Santiago Centro, 8330075, Santiago, Chile

    Rene Baudrand & Carlos E. Fardella

Authors
  1. Eugenio Arteaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Felipe Valenzuela
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carlos F. Lagos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marcela Lagos
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alejandra Martinez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rene Baudrand
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Cristian Carvajal
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Carlos E. Fardella
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eugenio Arteaga.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in the study were in accordance with the ethical standards of the Ethical Review Board of the School of Medicine of the Pontificia Universidad Católica de Chile and with the 1964 Helsinki declaration.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Arteaga, E., Valenzuela, F., Lagos, C.F. et al. Detection of a novel severe mutation affecting the CYP21A2 gene in a Chilean male with salt wasting congenital adrenal hyperplasia. Endocrine 67, 258–263 (2020). https://doi.org/10.1007/s12020-019-02097-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-019-02097-3

Keywords

Search

Navigation