Is There Any Clinical Relevant Difference Between Non Mosaic Klinefelter Syndrome Patients with or Without Androgen Receptor Variations?

Overview

Journal Sci Rep

Specialty Science

Date 2017 Jun 15

PMID 28611373

Authors

Umberto Valente

Cinzia Vinanzi

Savina Dipresa

Riccardo Selice

Massimo Menegazzo

Massimo Iafrate

Carlo Foresta

Andrea Garolla

Affiliations

Soon will be listed here.

Abstract

Klinefelter Syndrome (KS) is the most common chromosomal disorder in men leading to non-obstructive azoospermia. Spermatozoa can be found by TESE in about 50% of adults with KS despite severe testicular degeneration. We evaluated AR variations and polymorphism length in 135 non-mosaic KS patients, aimed to find possible correlation with clinical features, sex hormones and sperm retrieval. Among 135 KS patients we found AR variations in eight subjects (5.9%). All variations but one caused a single amino acid substitution. Four variations P392S, Q58L, L548F, A475V found in six patients had been previously described to be associated with different degrees of androgen insensitivity. Moreover we observed in two patients Y359F and D732D novel variations representing respectively a missense variation and a synonymous variation not leading to amino acid substitution. All the Klinefelter patients with AR gene variations were azoospermic. Spermatozoa were retrieved with TESE for two men (40%), sperm retrieval was unsuccessful in other 3 patients. This is the only study reporting AR variations in KS patients. Relevant clinical differences not emerged between AR mutated and not AR mutated KS patients, but does each variation play an important role in the trasmission to the offspring obtained by ART in this patients?

References

Rocca M, Pecile V, Cleva L, Speltra E, Selice R, Di Mambro A . The Klinefelter syndrome is associated with high recurrence of copy number variations on the X chromosome with a potential role in the clinical phenotype. Andrology. 2016; 4(2):328-34. DOI: 10.1111/andr.12146. View

Zinn A, Ramos P, Elder F, Kowal K, Samango-Sprouse C, Ross J . Androgen receptor CAGn repeat length influences phenotype of 47,XXY (Klinefelter) syndrome. J Clin Endocrinol Metab. 2005; 90(9):5041-6. DOI: 10.1210/jc.2005-0432. View

Gottlieb B, Beitel L, Nadarajah A, Paliouras M, Trifiro M . The androgen receptor gene mutations database: 2012 update. Hum Mutat. 2012; 33(5):887-94. DOI: 10.1002/humu.22046. View

Audi L, Fernandez-Cancio M, Carrascosa A, Andaluz P, Toran N, Piro C . Novel (60%) and recurrent (40%) androgen receptor gene mutations in a series of 59 patients with a 46,XY disorder of sex development. J Clin Endocrinol Metab. 2010; 95(4):1876-88. DOI: 10.1210/jc.2009-2146. View

Lund A, Juvonen V, Lahdetie J, Aittomaki K, Tapanainen J, Savontaus M . A novel sequence variation in the transactivation regulating domain of the androgen receptor in two infertile Finnish men. Fertil Steril. 2003; 79 Suppl 3:1647-8. DOI: 10.1016/s0015-0282(03)00256-5. View

Bhangoo A, Paris F, Philibert P, Audran F, Ten S, Sultan C . Isolated micropenis reveals partial androgen insensitivity syndrome confirmed by molecular analysis. Asian J Androl. 2010; 12(4):561-6. PMC: 3739378. DOI: 10.1038/aja.2010.6. View

Knoke I, Jakubiczka S, Lehnert H, Wieacker P . A new point mutation of the androgen receptor gene in a patient with partial androgen resistance and severe oligozoospermia. Andrologia. 1999; 31(4):199-201. DOI: 10.1046/j.1439-0272.1999.00278.x. View

Quigley C, De Bellis A, Marschke K, El-Awady M, Wilson E, French F . Androgen receptor defects: historical, clinical, and molecular perspectives. Endocr Rev. 1995; 16(3):271-321. DOI: 10.1210/edrv-16-3-271. View

Zuccarello D, Ferlin A, Vinanzi C, Prana E, Garolla A, Callewaert L . Detailed functional studies on androgen receptor mild mutations demonstrate their association with male infertility. Clin Endocrinol (Oxf). 2007; 68(4):580-8. DOI: 10.1111/j.1365-2265.2007.03069.x. View

10.

GOTTLIEB B, Beitel L, Lumbroso R, Pinsky L, Trifiro M . Update of the androgen receptor gene mutations database. Hum Mutat. 1999; 14(2):103-14. DOI: 10.1002/(SICI)1098-1004(1999)14:2<103::AID-HUMU2>3.0.CO;2-A. View

11.

Plotton I, Brosse A, Lejeune H . [Infertility treatment in Klinefelter syndrome]. Gynecol Obstet Fertil. 2011; 39(9):529-32. DOI: 10.1016/j.gyobfe.2011.07.002. View

12.

Bojesen A, Hertz J, Gravholt C . Genotype and phenotype in Klinefelter syndrome - impact of androgen receptor polymorphism and skewed X inactivation. Int J Androl. 2011; 34(6 Pt 2):e642-8. DOI: 10.1111/j.1365-2605.2011.01223.x. View

13.

Nahata L, Rosoklija I, Yu R, Cohen L . Klinefelter syndrome: are we missing opportunities for early detection?. Clin Pediatr (Phila). 2013; 52(10):936-41. DOI: 10.1177/0009922813493831. View

14.

Guo Z, Dai B, Jiang T, Xu K, Xie Y, Kim O . Regulation of androgen receptor activity by tyrosine phosphorylation. Cancer Cell. 2006; 10(4):309-19. DOI: 10.1016/j.ccr.2006.08.021. View

15.

Cheng J, Randall A, Baldi P . Prediction of protein stability changes for single-site mutations using support vector machines. Proteins. 2005; 62(4):1125-32. DOI: 10.1002/prot.20810. View

16.

Hiort O, Holterhus P, Horter T, Schulze W, Kremke B, Bals-Pratsch M . Significance of mutations in the androgen receptor gene in males with idiopathic infertility. J Clin Endocrinol Metab. 2000; 85(8):2810-5. DOI: 10.1210/jcem.85.8.6713. View

17.

Ferlin A, Vinanzi C, Garolla A, Selice R, Zuccarello D, Cazzadore C . Male infertility and androgen receptor gene mutations: clinical features and identification of seven novel mutations. Clin Endocrinol (Oxf). 2006; 65(5):606-10. DOI: 10.1111/j.1365-2265.2006.02635.x. View

18.

Skakkebaek N . Two types of tubules containing only Sertoli cells in adults with Klinefelter's syndrome. Nature. 1969; 223(5206):643-5. DOI: 10.1038/223643a0. View

19.

Trapman J, Klaassen P, Kuiper G, van der Korput J, Faber P, van Rooij H . Cloning, structure and expression of a cDNA encoding the human androgen receptor. Biochem Biophys Res Commun. 1988; 153(1):241-8. DOI: 10.1016/s0006-291x(88)81214-2. View

20.

Talebizadeh Z, Simon S, Butler M . X chromosome gene expression in human tissues: male and female comparisons. Genomics. 2006; 88(6):675-681. PMC: 7374763. DOI: 10.1016/j.ygeno.2006.07.016. View