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Chimeric Genes Causing 11β-Hydroxylase Deficiency: Implications in Clinical and Molecular Diagnosis

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Abstract

Deficiency of 11β-hydroxylase (11β-OHD) is the second most common cause of congenital adrenal hyperplasia (CAH), accounting for 0.2–8% of all cases. The disease is transmitted as an autosomal recessive trait and the underlying genetic causes of 11β-OHD are primarily small pathogenic variants affecting the CYP11B1 gene coding the 11β-hydroxylase enzyme. However, special events complicate the molecular diagnosis of 11β-OHD such as an unequal crossing over between the CYP11B2 (coding aldosterone synthase enzyme) and CYP11B1 genes. The resulting allele contains a hybrid gene, with a CYP11B2 5′-end and a CYP11B1 3′-end, where the CYP11B1 gene is under the control of the CYP11B2 promoter and thus not responding to the adrenocorticotropin (ACTH) but to angiotensin II and K+. This leads a reduction of cortisol production in 11β-OHD. In particular, CYP11B2/CYP11B1 chimeric genes can be distinguished into two groups depending on the breakpoint site: chimeras with breakpoint after the exon 5 of CYP11B2 preserve the aldosterone synthase activity, the others with breakpoint before exon 5 lose this function. In the last case, a more severe phenotype is expected. The aim of this review was to explore the setting of CYP11B2/CYP11B1 chimeras in 11β-OHD, performing a careful review of clinical literature cases.

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References

  1. Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, et al. Endocrine Society. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95:4133–60. https://doi.org/10.1210/jc.2009-2631.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Falhammar H, Thoren M. Clinical outcomes in the management of congenital adrenal hyperplasia. Endocrine. 2012;41:355–73. https://doi.org/10.1007/s12020-011-9591-x.

    Article  CAS  PubMed  Google Scholar 

  3. Bulsari K, Falhammar H. Clinical perspectives in congenital adrenal hyperplasia due to 11β-hydroxylase deficiency. Endocrine. 2017;55:19–36. https://doi.org/10.1007/s12020-016-1189-x.

    Article  CAS  PubMed  Google Scholar 

  4. White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev. 2000;21:245–91. https://doi.org/10.1210/edrv.21.3.0398.

    Article  CAS  PubMed  Google Scholar 

  5. Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet. 2005;365:2125–36. https://doi.org/10.1016/S0140-6736(05)66736-0.

    Article  PubMed  Google Scholar 

  6. Zachmann M, Tassinari D, Prader A. Clinical and biochemical variability of congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency. A study of 25 patients. J Clin Endocrinol Metab. 1983;56:222–9. https://doi.org/10.1210/jcem-56-2-222.

    Article  CAS  PubMed  Google Scholar 

  7. Nimkarn S, New MI. Steroid 11beta- hydroxylase deficiency congenital adrenal hyperplasia. Trends Endocrinol Metab. 2008;19:96–9. https://doi.org/10.1016/j.tem.2008.01.002.

    Article  CAS  PubMed  Google Scholar 

  8. Mornet E, Dupont J, Vitek A, White PC. Characterization of two genes encoding human steroid 11 beta-hydroxylase (P-450(11) beta). J Biol Chem. 1989;264:20961–7.

    Article  CAS  PubMed  Google Scholar 

  9. New MI, Seaman MP. Secretion rates of cortisol and aldosterone precursors in various forms of congenital adrenal hyperplasia. J Clin Endocrinol Metab. 1970;30:361–71. https://doi.org/10.1210/jcem-30-3-361.

    Article  CAS  PubMed  Google Scholar 

  10. Kayes-Wandover KM, Schindler RE, Taylor HC, White PC. Type 1 aldosterone synthase deficiency presenting in a middle-aged man. J Clin Endocrinol Metab. 2001;86:1008–12. https://doi.org/10.1210/jcem.86.3.7326.

    Article  CAS  PubMed  Google Scholar 

  11. Miao H, Yu Z, Lu L, Zhu H, Auchus RJ, Liu J, et al. Analysis of novel heterozygous mutations in the CYP11B2 gene causing congenital aldosterone synthase deficiency and literature review. Steroids. 2019;150: 108448. https://doi.org/10.1016/j.steroids.2019.108448.

    Article  CAS  PubMed  Google Scholar 

  12. Chabraoui L, Abid F, Menassa R, Gaouzi A, El Hessni A, Morel Y. Three novel CYP11B1 mutations in congenital adrenal hyperplasia due to steroid 11 beta-hydroxylase deficiency in a Moroccan population. Horm Res Paediatr. 2010;74:182–9. https://doi.org/10.1159/000281417.

    Article  CAS  PubMed  Google Scholar 

  13. Rösler A, Leiberman E, Cohen T. High frequency of congenital adrenal hyperplasia (classic 11 beta-hydroxylase deficiency) among Jews from Morocco. Am J Med Genet. 1992;42:827–34. https://doi.org/10.1002/ajmg.1320420617.

    Article  PubMed  Google Scholar 

  14. White PC. Steroid 11 beta-hydroxylase deficiency and related disorders. Endocrinol Metab Clin N Am. 2001;30(61–79):vi. https://doi.org/10.1016/s0889-8529(08)70019-7.

    Article  Google Scholar 

  15. Kandemir N, Yilmaz DY, Gonc EN, Ozon A, Alikasifoglu A, Dursun A, et al. Novel and prevalent CYP11B1 gene mutations in Turkish patients with 11-β hydroxylase deficiency. J Steroid Biochem Mol Biol. 2017;165:57–63. https://doi.org/10.1016/j.jsbmb.2016.03.006.

    Article  CAS  PubMed  Google Scholar 

  16. Curnow KM, Slutsker L, Vitek J, Cole T, Speiser PW, New MI, et al. Mutations in the CYP11B1 gene causing congenital adrenal hyperplasia and hypertension cluster in exons 6, 7, and 8. Proc Natl Acad Sci USA. 1993;90:4552–6. https://doi.org/10.1073/pnas.90.10.4552.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhao LQ, Han S, Tian HM. Progress in molecular-genetic studies on congenital adrenal hyperplasia due to 11beta-hydroxylase deficiency. World J Pediatr. 2008;4:85–90. https://doi.org/10.1007/s12519-008-0016-8.

    Article  CAS  PubMed  Google Scholar 

  18. Lifton RP, Dluhy RG, Powers M, Rich GM, Gutkin M, Fallo F, et al. Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase. Nat Genet. 1992;2:66–74. https://doi.org/10.1038/ng0992-66.

    Article  CAS  PubMed  Google Scholar 

  19. Pitsava G, Maria AG, Faucz FR. Disorders of the adrenal cortex: genetic and molecular aspects. Front Endocrinol (Lausanne). 2022;13: 931389. https://doi.org/10.3389/fendo.2022.931389.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Wu YC, Chen CI, Chen PY, Kuo CH, Hung YH, Peng KY, et al. GRAde: a long-read sequencing approach to efficiently identifying the CYP11B1/CYP11B2 chimeric form in patients with glucocorticoid-remediable aldosteronism. BMC Bioinform. 2022;22:613. https://doi.org/10.1186/s12859-022-04561-w.

    Article  CAS  Google Scholar 

  21. Halperin F, Dluhy RG. Glucocorticoid-remediable aldosteronism. Endocrinol Metab Clin N Am. 2011;40:333–41. https://doi.org/10.1016/j.ecl.2011.01.012.

    Article  CAS  Google Scholar 

  22. Portrat S, Mulatero P, Curnow KM, Chaussain JL, Morel Y, Pascoe L. Deletion hybrid genes, due to unequal crossing over between CYP11B1 (11beta-hydroxylase) and CYP11B2 (aldosterone synthase) cause steroid 11 beta-hydroxylase deficiency and congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2001;86:3197–201.

    CAS  PubMed  Google Scholar 

  23. Xu L, Xia W, Wu X, Wang X, Zhao L, Nie M. Chimeric CYP11B2/CYP11B1 causing 11β-hydroxylase deficiency in Chinese patients with congenital adrenal hyperplasia. Steroids. 2015;101:51–5. https://doi.org/10.1016/j.steroids.2015.06.002.

    Article  CAS  PubMed  Google Scholar 

  24. Duan L, Shen R, Song L, Liao Y, Zheng H. A novel chimeric CYP11B2/CYP11B1 combined with a new p.L340P CYP11B1 mutation in a patient with 11OHD: case report. BMC Endocr Disord. 2018;18:23. https://doi.org/10.1186/s12902-018-0249-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Xie H, Yin H, Ye X, Liu Y, Liu N, Zhang Y, et al. Detection of small CYP11B1 deletions and one founder chimeric CYP11B2/CYP11B1 gene in 11β-hydroxylase deficiency. Front Endocrinol (Lausanne). 2022;13: 882863. https://doi.org/10.3389/fendo.2022.882863.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Xiong Y, Zeng Z, Liang T, Yang P, Lu Q, Yang J, et al. Unequal crossing over between CYP11B2 and CYP11B1 causes 11 β-hydroxylase deficiency in a consanguineous family. J Steroid Biochem Mol Biol. 2023;233: 106375. https://doi.org/10.1016/j.jsbmb.2023.106375.

    Article  CAS  PubMed  Google Scholar 

  27. Hampf M, Dao NT, Hoan NT, Bernhardt R. Unequal crossing-over between aldosterone synthase and 11beta-hydroxylase genes causes congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2001;86:4445–52. https://doi.org/10.1210/jcem.86.9.7820.

    Article  CAS  PubMed  Google Scholar 

  28. Ezquieta B, Luzuriaga C. Neonatal salt-wasting and 11 beta-hydroxylase deficiency in a child carrying a homozygous deletion hybrid CYP11B2 (aldosterone synthase)-CYP11B1 (11 beta-hydroxylase). Clin Genet. 2004;66:229–35. https://doi.org/10.1111/j.1399-0004.2004.00291.x.

    Article  CAS  PubMed  Google Scholar 

  29. Kuribayashi I, Nomoto S, Massa G, Oostdijk W, Wit JM, Wolffenbuttel BH, et al. Steroid 11-beta-hydroxylase deficiency caused by compound heterozygosity for a novel mutation, p.G314R, in one CYP11B1 allele, and a chimeric CYP11B2/CYP11B1 in the other allele. Horm Res. 2005;63:284–93. https://doi.org/10.1159/000087074.

    Article  CAS  PubMed  Google Scholar 

  30. Menabò S, Boccassini S, Gambineri A, Balsamo A, Pasquali R, Prontera O, et al. Improving the diagnosis of 11β-hydroxylase deficiency using home-made MLPA probes: identification of a novel chimeric CYP11B2/CYP11B1 gene in a Sicilian patient. J Endocrinol Investig. 2016;39:291–5. https://doi.org/10.1007/s40618-015-0362-z.

    Article  CAS  Google Scholar 

  31. Curnow KM, Mulatero P, Emeric-Blanchouin N, Aupetit-Faisant B, Corvol P, Pascoe L. The amino acid substitutions Ser288Gly and Val320Ala convert the cortisol producing enzyme, CYP11B1, into an aldosterone producing enzyme. Nat Struct Biol. 1997;4:32–5. https://doi.org/10.1038/nsb0197-32.

    Article  CAS  PubMed  Google Scholar 

  32. Böttner B, Bernhardt R. Changed ratios of glucocorticoids/mineralocorticoids caused by point mutations in the putative I-helix regions of CYP11B1 and CYP11B2. Endocr Res. 1996;22:455–61. https://doi.org/10.1080/07435809609043731.

    Article  PubMed  Google Scholar 

  33. Böttner B, Denner K, Bernhardt R. Conferring aldosterone synthesis to human CYP11B1 by replacing key amino acid residues with CYP11B2-specific ones. Eur J Biochem. 1998;252:458–66. https://doi.org/10.1046/j.1432-1327.1998.2520458.x.

    Article  PubMed  Google Scholar 

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  1. Dipartimento di Scienze di Laboratorio e Infettivologiche, UOC Chimica, Biochimica e Biologia Molecolare Clinica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy

    Paola Concolino

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Concolino, P. Chimeric Genes Causing 11β-Hydroxylase Deficiency: Implications in Clinical and Molecular Diagnosis. Mol Diagn Ther 28, 215–224 (2024). https://doi.org/10.1007/s40291-024-00697-y

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