Skip to main content
SpringerLink
Log in

Three novel and two known androgen receptor gene mutations associated with androgen insensitivity syndrome in sex-reversed XY female patients

  • RESEARCH ARTICLE
  • Published:
Journal of Genetics Aims and scope Submit manuscript

Abstract

Molecular characterization of 23 cytogenetically confirmed XY females was attempted by screening coding regions of SRY and androgen receptor (AR) genes. Five of the index cases showed sequence variations in various exons of the AR gene: a deletion (n.1911delG) and substitutions n.1761G >A and n.1317C >T in exon 1; n.3510C >T transition in exon 6 and deletion mutation (n.3672delT) in exon 7. Four mutations identified here lead to the formation of truncated receptor protein, involving a substantial loss of AR functional domains which explains the phenotype in the subjects. The n.1761G >A substitution has been previously reported in cases with mild androgen insensitivity. Although the ligand-binding domain was considered as the mutational hot spot in AR gene, we report here 3/5 variations in the N-terminal domain emphasizing the significance of considering the N-terminal domain of AR as well for mutation screening. Our present observation also strengthens the role of AR gene and its direct association with AIS.

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.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  • Ahmed S. F., Cheng A., Dovey L., Hawkins J. R., Martin H., Rowland J. et al. 2000 Phenotypic features, androgen receptor binding, and mutational analysis in 278 clinical cases reported as androgen insensitivity syndrome. J. Clin. Endocrinol. Metab. 85, 658–665.

    CAS  PubMed  Google Scholar 

  • Audi L., Fernández-Cancio M., Carrascosa A., Andaluz P., Torán N., Piró C. et al. 2010 Novel (60%) and recurrent (40%) androgen receptor gene mutations in series of 59 patients with a 46,XY disorder of sex development. J. Clin. Endocrinol. Metab. 95, 1876–1888.

    Article  CAS  PubMed  Google Scholar 

  • Bagatell C. J. and Bremner W. J. 2003 Androgens in health and disease, 1st edition. Springer Science + Business Media, New York, USA.

    Book  Google Scholar 

  • Boyer A., Dornan S., Daneau I., Lussier J. and Silversides D. W. 2002 Conservation of the function of DMRT1 regulatory sequences in mammalian sex differentiation. Genesis 34, 236–243.

    Article  CAS  PubMed  Google Scholar 

  • Brinkmann A. O. 2001 Molecular basis of androgen insensitivity. Mol. Cell. Endocrinol. 179, 105–109.

    Article  CAS  PubMed  Google Scholar 

  • Canto P., Vilchis F., Soderlund D., Reyes E. and Mendez J. P. 2005 A heterozygous mutation in the desert hedgehog gene in patients with mixed gonadal dysgenesis. Mol. Hum. Reprod. 11, 833–836.

    Article  CAS  PubMed  Google Scholar 

  • Centenera M. M., Harris J. M., Tilley W. D. and Butler L. M. 2008 The contribution of different androgen receptor domains to receptor dimerization and signaling. Mol. Endocrinol 22, 2373–2382.

    Article  CAS  PubMed  Google Scholar 

  • Cheikhelard A., Morel Y., Thibaud E., Lortat-Jacob S., Jaubert F., Polak M. et al. 2008 Long-term followup and comparison between genotype and phenotype in 29 cases of complete androgen insensitivity syndrome. J. Urol. 180, 1496–1501.

    Article  PubMed  Google Scholar 

  • Deeb A., Mason C., Lee Y. S. and Hughes I. A. 2005 Correlation between genotype, phenotype and sex of rearing in 111 patients with partial androgen insensitivity syndrome. Clin. Endocrinol. (Oxf) 63, 56–62.

    Article  CAS  Google Scholar 

  • DiNapoli L., Batchvarov J. and Capel B. 2006 FGF9 promotes survival of germ cells in the fetal testis. Development 133, 1519–1527.

    Article  CAS  PubMed  Google Scholar 

  • Dowsing A. T., Yong E. L., Clark M., McLachlan R. I, de Kretser D. M. and Trounson A. O 1999 Linkage between male infertility and trinucleotide repeat expansion in the androgen-receptor gene. Lancet 354, 640–643.

    Article  CAS  PubMed  Google Scholar 

  • Evans B. A., Hughes I. A., Bevan C. L., Patterson M. N. and Gregory J. W. 1997 Phenotypic diversity in siblings with partial androgen insensitivity syndrome. Arch. Dis. Child. 76, 529–531.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Galani A., Sofocleous C., Karahaliou F., Papathanasiou A., Kitsiou-Tzeli S. and Kalpini-Mavrou A. 2008 Sex-reversed phenotype in association with two novel mutations c.2494delA and c.T3004C in the ligand-binding domain of the androgen receptor gene. Fertil. Steril. 90, e1–e4.

    Article  Google Scholar 

  • Gottlieb B., Beitel L. K., Wu J. H. and Trifiro M. 2004 The androgen receptor gene mutations database (ARDB): 2004 update. Hum. Mutat. 23, 527–533.

    Article  CAS  PubMed  Google Scholar 

  • Gottlieb B., Beitel L. K., Nadarajah A., Paliouras M. and Trifiro M. 2012 The androgen receptor gene mutations database: 2012 update. Hum. Mutat. 33, 887–894.

    Article  CAS  PubMed  Google Scholar 

  • Goulis D. G., Iliadou P. K., Papanicolaou A., Georgiou I., Chatzikyriakidou A., Gerou S. et al. 2006 R831X mutation of the androgen receptor gene in an adolescent with complete androgen insensitivity syndrome and bilateral testicular hamartomata. Hormones (Athens) 5, 200–204.

    Article  Google Scholar 

  • He B. and Wilson E. M. 2003 Electrostatic modulation in steroid receptor recruitment of LXXLL and FXXLF motifs. Mol. Biol. 23, 2135–2150.

    CAS  Google Scholar 

  • Hungerford D. A. 1965 Leucocytes cultured from small inocula of whole blood and the preparation of metaphase chromosomes by treatment with hypotonic KCl. Stain Technol. 40, 333–338.

    Article  CAS  PubMed  Google Scholar 

  • Ignacak M., Niedziela M. and Trzeciak W. H. 2002 Transition C2718T in the AR gene, resulting in generation of a termination codon and truncated form of the androgen receptor, causes complete androgen insensitivity syndrome. J. Appl. Genet. 43, 109–114.

    PubMed  Google Scholar 

  • Ignacak M., Turek-Plewa J., Limon J. and Trzeciak W. H. 2004 A novel c.C2754 >T transition in the androgen receptor gene introduces the premature termination codon Q798X and results in a truncated form of the receptor. Gynecol. Endocrinol. 19, 178–181.

    Article  CAS  PubMed  Google Scholar 

  • Imasaki K., Okabe T., Murakami H., Fujita K., Takayanagi R. and Nawata H. 1995 Premature termination mutation (772Glu– > stop) in the hormone-binding domain of the androgen receptor in a patient with the receptor-negative form of complete androgen insensitivity syndrome. Endocr. J. 42, 643–648.

    Article  CAS  PubMed  Google Scholar 

  • Isidor B., Capito C., Paris F., Baron S., Corradini N. and Cabaret B. 2009 Familial frameshift SRY mutation inherited from a mosaic father with testicular dysgenesis syndrome. J. Clin. Endocrinol. Metab. 94, 3467–3471.

    Article  CAS  PubMed  Google Scholar 

  • Jorgensen P. B., Kjartansdóttir K. R. and Fedder J. 2010 Care of women with XY karyotype: a clinical practice guideline. Fertil. Steril. 94, 105–113.

    Article  PubMed  Google Scholar 

  • Katoh-Fukui Y., Tsuchiya R., Shiroishi T., Nakahara Y., Hashimoto N., Noguchi K. et al. 1998 Male-to-female sex reversal in M33 mutant mice. Nature 393, 688–692.

    Article  CAS  PubMed  Google Scholar 

  • La Spada A. R., Wilson E. M., Lubahn D. B., Harding A. E. and Fischbeck K. H. 1991 Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352, 77–79.

    Article  CAS  PubMed  Google Scholar 

  • Layman L. C., Tho S. P., Clark A. D., Kulharya A. and McDonough P. G. 2009 Phenotypic spectrum of 45,X/46,XY males with a ring Y chromosome and bilaterally descended testes. Fertil. Steril. 91, 791–797.

    Article  PubMed  Google Scholar 

  • Li J., Fu J., Toumazou C., Yoon H. G. and Wong J. 2006 A role of the amino-terminal (N) and carboxyl-terminal (C) interaction in binding of androgen receptor to chromatin. Mol. Endocrinol. 20, 776–785.

    Article  CAS  PubMed  Google Scholar 

  • Liu Q., Hong J., Cui B., Zhang Y., Gu W., Chi Z. et al. 2008 Androgen receptor gene CAG(n) trinucleotide repeats polymorphism in Chinese women with polycystic ovary syndrome. Endocrine 33, 165–170.

    Article  CAS  PubMed  Google Scholar 

  • McEwan I. J. 2009 Nuclear receptors: one big family. Methods Mol. Biol. 505, 3–18.

    Article  CAS  PubMed  Google Scholar 

  • McElreavy K., Vilain E., Abbas N., Costa J. M., Pouleyreau N., Kucheria K. et al. 1992 XY sex reversal associated with a deletion 50 to the SRY “HMG box” in the testis-determining region. Proc. Natl. Acad. Sci. USA 89, 11016–11020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Melo C. O., Silva D. M. and da Cruz A. D. 2011 Challenges in clinical and laboratory diagnosis of androgen insensitivity syndrome: a case report. J. Med. Case Rep. 5, 446.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ocal G., Berberoğlu M., Sıklar Z., Ruhi H. I., Tükün A., Camtosun E. et al. 2012 The clinical and genetic heterogeneity of mixed gonadal dysgenesis: does “disorders of sexual development (DSD)” classification based on new Chicago consensus cover all sex chromosome DSD?. Eur. J. Pediatr. 171, 1497–1502.

    Article  PubMed  Google Scholar 

  • Petroli R. J., Maciel-Guerra A. T., Soardi F. C., de Calais F. L., Guerra-Junior G. and de Mello M. P. 2011 Severe forms of partial androgen insensitivity syndrome due to p.L830F novel mutation in androgen receptor gene in a Brazilian family. BMC Res. Notes 4, 173.

    Article  PubMed  PubMed Central  Google Scholar 

  • Philibert P., Audran F., Pienkowski C., Morange I., Kohler B., Flori E. et al. 2010 Complete androgen insensitivity syndrome is frequently due to premature stop codons in exon 1 of the androgen receptor gene: an international collaborative report of 13 new mutations. Fertil. Steril. 94, 472–476.

    Article  CAS  PubMed  Google Scholar 

  • Poukka H., Karvonen U., Yoshikawa N., Tanaka H., Palvimo J. J. and Janne O. A. 2000 The RING finger protein SNURF modulates nuclear trafficking of the androgen receptor. J. Cell Sci. 113, 2991–3001.

    CAS  PubMed  Google Scholar 

  • Raicu F., Giuliani R., Gatta V., Palka C., Franchi P. G., Lelli-Chiesa P. et al. 2008 Novel mutation in the ligand-binding domain of the androgen receptor gene (l790p) associated with complete androgen insensitivity syndrome. Asian J. Androl. 10, 687–691.

    Article  PubMed  Google Scholar 

  • Rocha V. B., Guerra-Júnior G., Marques-de-Faria A. P., de Mello M. P. and Maciel-Guerra A. T. 2011 Complete gonadal dysgenesis in clinical practice: the 46,XY karyotype accounts for more than one third of cases. Fertil. Steril. 96, 1431–1434.

    Article  PubMed  Google Scholar 

  • Seabright M. 1971 A rapid banding technique for human chromosomes. Lancet 2, 971–972.

    Article  CAS  PubMed  Google Scholar 

  • Shahid M., Dhillion V. S., Jain N., Hedau S., Diwakar S., Sachdeva P. et al. 2004 Two new novel point mutations localized upstream and downstream of the HMG box region of the SRY gene in three Indian 46,XY females with sex reversal and gonadal tumour formation. Mol. Hum. Reprod. 10, 521–526.

    Article  CAS  PubMed  Google Scholar 

  • Shahid M., Dhillon V. S., Khalil H. S., Haque S., Batra S., Husain S. A. et al. 2010 A SRY-HMG box frame shift mutation inherited from a mosaic father with a mild form of testicular dysgenesis syndrome in Turner syndrome patient. BMC Med. Genet. 11, 131.

    Article  PubMed  PubMed Central  Google Scholar 

  • Sultan C., Paris F., Terouanne B., Balaguer P., Georget V., Poujol N. et al. 2001 Disorders linked to insufficient androgen action in male children. Hum. Reprod. Update 7, 314–322.

    Article  CAS  PubMed  Google Scholar 

  • Sun S., Luo F., Zhou Z. and Wu W. 2010 A novel androgen receptor gene mutation in a Chinese patient with complete androgen insensitivity syndrome. Eur. J. Obstet. Gynecol. Reprod. Biol. 153, 173–175.

    Article  CAS  PubMed  Google Scholar 

  • Thompson J., Saatcioglu F., Jänne O. A. and Palvimo J. J. 2001 Disrupted amino- and carboxyl-terminal interactions of the androgen receptor are linked to androgen insensitivity. Mol. Endocrinol. 15, 923–935.

    Article  CAS  PubMed  Google Scholar 

  • Tilley W. D., Buchanan G., Hickey T. E. and Bentel J. M. 1996 Mutations in the androgen receptor gene are associated with progression of human prostate cancer to androgen independence. Clin. Cancer Res. 2, 277–285.

    CAS  PubMed  Google Scholar 

  • Wang Q., Ghadessy F. J. and Yong E. L. 1998 Analysis of the transactivation domain of the androgen receptor in patients with male infertility. Clin. Genet. 54, 185–192.

    Article  CAS  PubMed  Google Scholar 

  • Wooster R., Mangion J., Eeles R., Smith S., Dowsett M., Averill D. et al. 1992 A germline mutation in the androgen receptor gene in two brothers with breast cancer and Reifenstein syndrome. Nat. Genet. 2, 132–134.

    Article  CAS  PubMed  Google Scholar 

  • Zoppi S., Wilson C. M., Harbison M. D., Griffin J. E., Wilson J. D., McPhaul M. J. et al. 1993 Complete testicular feminization caused by an amino-terminal truncation of the androgen receptor with downstream initiation. J. Clin. Invest. 91, 1105–1112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the patients and their family members for their cooperation and acknowledge the grant support of UGC Major Research project (F. no. 39-113/2010 SR), UGC-SAP DRS1 (F.3-3/2007), UGC-infrastructure, UPE II, DST-FIST to Department of Genetics. BS is grateful to Lady Tata Memorial Trust, Mumbai and UGC-BSR for fellowship assistance.

Author information

Authors and Affiliations

  1. Department of Genetics, Dr. ALMPG Institute of Basic Medical Sciences, University of Madras, Taramani, Chennai, 600 113, India

    BALACHANDRAN SARANYA, GUNASEKARAN BHAVANI, BRINDHA ARUMUGAM & SATHIYAVEDU THYAGARAJAN SANTHIYA

  2. Department of Medical Genetics, Institute of Obstetrics and Gynecology, Madras Medical College, Government Hospital for Women and Children, Egmore, Chennai, 600 008, India

    MEENA JAYASHANKAR

Authors
  1. BALACHANDRAN SARANYA
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. GUNASEKARAN BHAVANI
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. BRINDHA ARUMUGAM
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. MEENA JAYASHANKAR
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. SATHIYAVEDU THYAGARAJAN SANTHIYA
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to SATHIYAVEDU THYAGARAJAN SANTHIYA.

Additional information

Corresponding editor: Rajiva Raman

Balachandran S., Gunasekaran B., Arumugam B., Jayashankar M. and Santhiya S. T. 2016 Three novel and two known androgen receptor gene mutations associated with androgen insensitivity syndrome in sex-reversed XY female patients. J. Genet. 95, xx–xx

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

SARANYA, B., BHAVANI, G., ARUMUGAM, B. et al. Three novel and two known androgen receptor gene mutations associated with androgen insensitivity syndrome in sex-reversed XY female patients. J Genet 95, 911–921 (2016). https://doi.org/10.1007/s12041-016-0716-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12041-016-0716-0

Keywords

Search

Navigation