Skip to main content
SpringerLink
Log in

New mutations, hotspots, and founder effects in Brazilian patients with steroid 5α-reductase deficiency type 2

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Mutations of the steroid 5α-reductase type 2 (SRD5A2) gene in 46,XY subjects cause masculinization defects of varying degrees, due to reduced or impaired enzymatic activity. In this study, sequence abnormalities of the SRD5A2 gene were assessed by polymerase chain reaction with specific primers and automated sequencing analysis in DNA samples from 20 patients with suspected steroid 5α-reductase type 2 deficiency from 18 Brazilian families. Eleven subjects presented SRD5A2 homozygous single-base mutations (two first cousins and four unrelated patients with G183S, two with R246W, one with del642T, one with G196S, and one with 217_218insC plus the A49T variant in heterozygosis), whereas four were compound heterozygotes (one with Q126R/IVS3+1G>A, one with Q126R/del418T, and two brothers with Q126R/G158R). Three patients were heterozygous for A207D, G196S, and R266W substitutions. The V89L polymorphism was found in heterozygosis in one of them (with A207D) and in one case with an otherwise normal gene sequence. The A49T variant was also detected in heterozygosis in the second case without other sequencing abnormalities. Four patients harbor yet non-described SRD5A2 gene mutations: a single nucleotide deletion (del642T), a G158R amino acid substitution, a splice junction mutation (IVS3+1G>A), and the insertion of a cytosine (217_218insC) occurring at a CCCC motif. This is the first report of a single-nucleotide insertion in the coding sequence of the SRD5A2 gene. In addition to these new mutations, this investigation reveals the prevalence of G183S substitution among a subset of African–Brazilian patients and presents evidences of the recurrence of already known mutations.

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

Similar content being viewed by others

References

  1. Wilson JD, Griffin JE, Russell DW (1993) Steroid 5 alpha-reductase 2 deficiency. Endocr Rev 14:577–593

    Article  CAS  PubMed  Google Scholar 

  2. Odame I, Donaldson MD, Wallace AM, Cochran W, Smith PJ (1992) Early diagnosis and management of 5 alpha-reductase deficiency. Arch Dis Child 67:720–723

    Google Scholar 

  3. Saenger P, Goldman AS, Levine LS, Korth-Schutz S, Muecke EC, Katsumata M, Doberne Y, New MI (1978) Prepubertal diagnosis of steroid 5 alpha-reductase deficiency. J Clin Endocrinol Metab 46:627–634

    Google Scholar 

  4. Greene S, Zachmann M, Manella B, Hesse V, Hoepffner W, Willgerodt H, Prader A (1987) Comparison of two tests to recognize or exclude 5 alpha-reductase deficiency in prepubertal children. Acta Endocrinol (Copenh) 114:113–117

    Google Scholar 

  5. Imperato-McGinley J, Zhu YS (2002) Androgens and male physiology the syndrome of 5 alpha-reductase-2 deficiency. Mol Cell Endocrinol 198:51–59

    Google Scholar 

  6. Zucker KJ (1999) Intersexuality and gender identity differentiation. Annu Rev Sex Res 10:1–69

    Google Scholar 

  7. Sinnecker GH, Hiort O, Dibbelt L, Albers N, Dorr HG, Hauss H, Heinrich U, Hemminghaus M, Hoepffner W, Holder M, Schnabel D, Kruse K (1996) Phenotypic classification of male pseudohermaphroditism due to steroid 5 alpha-reductase 2 deficiency. Am J Med Genet 63:223–230

    Google Scholar 

  8. Nordenskjold A, Ivarsson S-A (1998) Molecular characterization of 5 alpha-reductase type 2 deficiency and fertility in a Swedish family. J Clin Endocrinol Metabol 83:3236–3238

    Google Scholar 

  9. Human Gene Mutation Database SRD5A2 gene (http://uwcmml1s.uwcm.ac.uk/uwcm/mg/search/127343.html). Accessed September 28, 2004

  10. Fernandez-Cancio M, Nistal M, Gracia R, Molina MA, Tovar JA, Esteban C, Carrascosa A, Audi L (2004) Compound heterozygous mutations in the SRD5A2 gene exon 4 in a male pseudohermaphrodite patient of Chinese origin. J Androl 25:412–416

    Google Scholar 

  11. Wang Y, Li Q, Xu J, Liu Q, Wang W, Lin Y, Ma F, Chen T, Li S, Shen Y (2004) Mutation analysis of five candidate genes in Chinese patients with hypospadias. Eur J Hum Genet 12:706–712

    Google Scholar 

  12. Silver RI, Russell DW (1999) 5 alpha-reductase type 2 mutations are present in some boys with hypospadias. J Urol 162:1142–1145

    Google Scholar 

  13. Katz MD, Cai LQ, Zhu Y, Herrera C, DeFillo-Ricart M, Shackleton HL, Imperato-McGinley J (1995) The biochemical and phenotypic characterization of females homozygous for 5 alpha-reductase deficiency. J Clin Endocrinol Metab 80:3160–3167

    Google Scholar 

  14. Ferraz LFC, Guerra Jr G, Baptista MTM, Maciel-Guerra AT, Hackel C (1998) Detection of Gly-196-Ser mutation in 5 alpha-reductase type II gene in a Brazilian patient with female assignment and behavior. J Pediatr Endocrinol Metab 11:465–466

    Google Scholar 

  15. Ferraz LFC, Baptista MTM, Maciel-Guerra AT, Guerra Jr G, Hackel C (1999) New frameshift mutation in the 5 alpha-reductase type 2 gene in a Brazilian patient with 5 alpha-reductase deficiency. Am J Med Genet 87:221–225

    Google Scholar 

  16. Bortolini MC, Salzano FM, Zago MA, Da Silva WA Jr, Weimer TA (1997) Genetic variability in two Brazilian ethnic groups: a comparison of mitochondrial and protein data. Am J Phys Anthropol 103:147–156

    Google Scholar 

  17. Levy MA, Brandt M, Sheedy KM, Holt DA, Heaslip JI, Trill JJ, Ryan PJ, Morris RA, Garrison LM, Bergsma DJ (1995) Cloning, expression and functional characterization of type 1 and type 2 steroid 5 alpha-reductases from Cynomolgus monkey: comparisons with human and rat isoenzymes. J Steroid Biochem Mol Biol 52:307–319

    Google Scholar 

  18. Wigley WC, Prihoda JS, Mowszowicz I, Mendonca BB, New MI, Wilson JD, Russell DW (1994) Natural mutagenesis study of the human steroid 5 alpha-reductase 2 isozyme. Biochemistry 33:1265–1270

    Google Scholar 

  19. Mendonça BB, Inácio M, Costa EM, Arnhold IJ, Silva FA, Nicolau W, Bloise W, Russell DW, Wilson JD (1996) Male pseudohermaphroditism due to steroid 5 alpha-reductase 2 deficiency. Diagnosis, psychological evaluation, and management. Medicine (Baltimore) 75:64–76

    Google Scholar 

  20. Cai LQ, Zhu YS, Katz MD, Herrera C, Baez J, DeFillo-Ricart M, Shackleton CH, Imperato-McGinley J (1996) 5 alpha-reductase-2 gene mutations in the Dominican Republic. J Clin Endocrinol Metab 81:1730–1735

    Google Scholar 

  21. Weil TE, Black JK, Blutstein HI, Johnston KT, McMorris DS Munson FP (1973) Social System. In: Area handbook for the Dominican Republic. US Government Printing Office, Superintendent of Documents, 2nd edn, pp 49–55

  22. Russell DW, Wilson JD (1994) Steroids 5 alpha-reductases: two genes/two enzymes. Annu Rev Biochem 63:25–61

    CAS  PubMed  Google Scholar 

  23. Boudon C, Lumbroso S, Lobaccaro JM, Szarras-Czapnik M, Romer TE, Garandeau P, Montoya P, Sultan C (1995) Molecular study of the 5 alpha-reductase type 2 gene in three European families with 5α-reductase deficiency. J Clin Endocrinol Metab 80:2149–2153

    Google Scholar 

  24. Thigpen AE, Davis DI, Milatovich A, Mendonca BB, Imperato-McGinley J, Griffin JE, Francke U, Wilson JD, Russell DW (1992) Molecular genetics of 5 alpha-reductase deficiency. J Clin Invest 90:799–809

    Google Scholar 

  25. Canto P, Vilchis F, Chavez B, Mutchinick O, Imperato-McGinley J, Perez-Palacios G, Ulloa-Aguirre A, Mendez JP (1997) Mutations of the 5 alpha-reductase type 2 gene in eight Mexican patients from six different pedigrees with 5α-reductase-2 deficiency. Clin Endocrinol 46:155–160

    Google Scholar 

  26. Makridakis NM, Ross RK, Pike MC, Chang L, Stanczik FZ, Kolonel LN, Shi C-Y, Yu MC, Henderson BE, Reichardt JKV (1997) A prevalent missense substitution that modulates activity of prostatic steroid 5 alpha-reductase. Cancer Res 57:1020–1022

    Google Scholar 

  27. Andersson S, Berman DH, Jenkins EP, Russell DW (1991) Deletion of steroid 5 alpha-reductase 2 gene in male pseudohermaphroditism. Nature 354:159–161

    Google Scholar 

  28. Hiort O, Schütt MS, Bals-Pratsch MT, Holterhus P-M, Marschke C, Struve D (2002) A novel homozygous disruptive mutation in the SRD5A2 gene in a partially virilized patient with 5 alpha-reductase deficiency. Int J Androl 25:55–58

    Google Scholar 

  29. Cooper DN (1990) Structure and function in the human genome. In: Cooper DN (ed) Human gene evolution. BIOS Scientific, Guilford, UK, pp 3–54

    Google Scholar 

  30. Nishizawa M, Nishizawa K (2002) A DNA sequence evolution analysis generalized by simulation and the Markov chain Monte Carlo method implicates strand slippage in a majority of insertions and deletions. J Mol Evol 55:706–717

    Google Scholar 

  31. Makridakis NM, Ross RK, Pike MC, Crocitto LE, Kolonel LN, Pearce CL, Henderson BE, Reichardt JKV (1999) A missense substitution in the SRD5A2 gene is associated with prostate cancer in African–American and Latino men in Los Angeles. Lancet 354:957–958

    Google Scholar 

  32. Allen NE, Reichardt JKV, Nguyen H, Key TJ (2003) Association between two polymorphisms in the SRD5A2 gene and serum androgen concentrations in British men. Cancer Epidemiol Biomark Prev 12:578–581

    Google Scholar 

  33. Kim KS, Liu W, Cunha GR, Russell DW, Huang H, Shapiro E, Baskin LS (2002) Expression of the androgen receptor and 5 alpha-reductase type 2 in the developing human fetal penis and urethra. Cell Tissue Res 307:145–153

    Google Scholar 

Download references

Acknowledgements

We wish to thank Drs. Leandra Steinmetz and Durval Damiani from Instituto da Criança, Faculdade de Medicina, Universidade de Sao Paulo (USP), Sao Paulo, SP, for referral of patient no. 16 and to Dr. Laurione Candido de Oliveira from Departamento de Patologia Clínica, Faculdade de Ciencias Medicas, Universidade Estadual de Campinas, Campinas, SP, for re-evaluation of hormonal data. This research was supported by grants to G.G.-Jr. from Conselho Nacional de Pesquisa (CNPq 472638/2003-3). C.H. and G.G.-Jr. were recipients of research fellowships from CNPq and L.E.C.O. was the recipient of an undergraduate fellowship from Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP 02/13237-4).

Author information

Authors and Affiliations

  1. Centro de Biologia Molecular e Engenharia Genetica, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil

    Christine Hackel, Luiz Eduardo Chimello Oliveira, Lucio Fabio Caldas Ferraz & Maria Manuela Oliveira Tonini

  2. Departamento de Genetica Medica, Faculdade de Ciencias Medicas CP6111, Universidade Estadual de Campinas (UNICAMP), 13083-970, Campinas, SP, Brazil

    Christine Hackel

  3. Grupo Interdisciplinar de Estudos da Determinacao e Diferenciacao do Sexo, Faculdade de Ciencias Medicas, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil

    Christine Hackel, Eliana Gabas Stuchi-Perez & Gil Guerra-Junior

  4. Departamento de Pediatria, Faculdade de Medicina, Universidade Federal da Bahia (UFBA), Salvador, BA, Brazil

    Daniela Nunes Silva & Maria Betania Toralles

  5. Departamento de Pediatria, Faculdade de Ciencias Medicas, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil

    Gil Guerra-Junior

Authors
  1. Christine Hackel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luiz Eduardo Chimello Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lucio Fabio Caldas Ferraz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maria Manuela Oliveira Tonini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daniela Nunes Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maria Betania Toralles
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eliana Gabas Stuchi-Perez
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gil Guerra-Junior
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christine Hackel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hackel, C., Oliveira, L.E.C., Ferraz, L.F.C. et al. New mutations, hotspots, and founder effects in Brazilian patients with steroid 5α-reductase deficiency type 2. J Mol Med 83, 569–576 (2005). https://doi.org/10.1007/s00109-005-0651-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-005-0651-7

Keywords

Search

Navigation