- Open Access
Is a genetic defect in Fkbp6 a common cause of azoospermia in humans?
Cellular & Molecular Biology Letters volume 11, pages557–569(2006)
FK506-binding protein 6 (Fkbp6) is a member of a gene family containing a prolyl isomerase/FK506-binding domain and tetratricopeptide protein-protein interaction domains. Recently, the targeted inactivation of Fkbp6 in mice has been observed to result in aspermic males and the absence of normal pachytene spermatocytes. The loss of Fkbp6 results in abnormal pairing and a misalignment of the homologous chromosomes, and in non-homologous partner switches and autosynapsis of the X chromosome cores in meiotic spermatocytes. In this study, we analyzed whether human FKBP6 gene defects might be associated with human azoospermia. We performed a mutation analysis in all the coding regions of the human FKBP6 gene in 19 patients with azoospermia resulting from meiotic arrest. The expression of the human FKBP6 gene was specific to the testis, and a novel polymorphism site, 245C → G (Y60X) could be found in exon 3. Our findings suggest that the human FKBP6 gene might be imprinted in the testis based on an analysis using two polymorphism sites.
deleted in azoospermia
FK506-binding protein 6
RNA-binding motif; Y chromosome
reverse transcription-polymerase chain reaction
ubiquitin-specific protease 9 gene on the Y
Meng, X., Lu, X., Morris, C.A. and Keating, M.T. A novel human FKBP6 is deleted in Williams syndrome. Genomics l52 (1998) 130–137.
Crackower, M.A., Kolas, N.K., Noguchi, J., Sarao, R., Kikuchi, K., Kaneko, H., Kobayashi, E., Kawai, Y., Kozieradzki, I., Landers, R., Mo, R., Hui, C.C., Nieves, E., Cohen, P,E., Osborne, L.R., Wada, T., Kunieda, T., Moens, P.B. and Penninger, J.M. Essential role of Fkbp6 in male fertility and homologous chromosome pairing in meiosis. Science 300 (2003) 1291–1295.
Ikadai, H., Noguchi, J., Yoshida, M. and Imamichi, T. An aspermia rat mutant (as/as) with spermatogenic failure at meiosis. J. Vet. Med. Sci. 54 (1992) 745–749.
Atagi, Y., Ikadai, H., Kurohmaru, M. and Hayashi, Y. Testicular disruption in the As (aspermia) mutant rat, with special reference to the aggregate of ribosomes. J. Vet. Med. Sci. 55 (1993) 301–306.
Noguchi, J., Kobayashi, E., Shimada, A., Kikuchi, K., Kaneko, H., Takahashi, H., Ikadai, H. and Kunieda, T. A locus responsible for arrest of spermatogenesis is located on rat chromosome 12. Mamm. Genome 10 (1999) 189–190.
Zickler, D. and Kleckner, N. Meiotic chromosomes: integrating structure and function. Annu. Rev. Genet. 33 (1999) 603–754.
Yuan, L., Liu, J.G., Zhao, J., Brundell, E., Daneholt, B. and Hoog, C. The murine SCP3 gene is required for synaptonemal complex assembly, chromosome synapsis, and male fertility. Mol. Cell 5 (2000) 73–83.
Yuan, L., Liu, J.G., Hoja, M.R., Wilbertz, J., Nordqvist, K. and Hoog, C. Female germ cell aneuploidy and embryo death in mice lacking the meiosis-specific protein SCP3. Science 296 (2002) 1115–1118.
Miyamoto, T., Hasuike, S., Yogev, L., Maduro, M.R., Ishikawa, M., Westphal, H. and Lamb, D.J. Azoospermia in patients heterozygous for a mutation in SYCP3. Lancet 362 (2003) 1714–1719.
Reijo, R., Lee, T.Y., Salo, P., Alagappan, R., Brown, L.G., Rosenberg, M., Rozen, S., Jaffe, T., Straus, D., Hovatta, O., de la Chapelle, A., Silber, S. and Page, D.C. Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene. Nat. Genet. 10 (1995) 383–393.
Elliott, D.J., Millar, M.R., Oghene, K., Ross, A., Kiesewetter, F., Pryor, J., McIntyre, M., Hargreave, T.B., Saunders, P.T., Vogt, P.H., Chandley, A.C. and Cooke, H. Expression of RBM in the nuclei of human germ cells is dependent on a critical region of the Y chromosome long arm. Proc. Natl. Acad. Sci. USA 94 (1997) 3848–3853.
Sun, C., Skaletsky, H., Birren, B., Devon, K., Tang, Z., Silber, S., Oates, R. and Page, D.C. An azoospermic man with a de novo point mutation in the Y-chromosomal gene USP9Y. Nat. Genet. 23 (1999) 429–432.
Matzuk, M.M. and Lamb, D.J. Genetic Dissection of Mammalian Fertility Pathways. Nat. Med. 8(S1) (2002) S41–S49.
Nakamura, Y., Kitamura, M., Nishimura, K., Koga, M., Kondoh, N., Takeyama, M., Matsumiya, K. and Okuyama, A. Chromosomal variants among 1790 infertile men. Int. J. Urol. 8 (2001) 49–52.
Lejeune, F. and Maquat, L.E. Mechanistic links between nonsense-mediated mRNA decay and pre-mRNA splicing in mammalian cells. Curr. Opin. Cell Biol. 17 (2005) 309–315.
Ozaki, K., Ohnishi, Y., Iida, A., Sekine, A., Yamada, R., Tsunoda, T., Sato, H., Sato, H., Hori, M., Nakamura, Y. and Tanaka, T. Functional SNPs in the lymphotoxin-α gene that are associated with susceptibility to myocardial infarction. Nat. Genet. 32 (2002) 650–654.
Westerveld, G.H., Repping, S., Lombardi, M.P. and van der Veen, F. Mutations in the chromosome pairing gene FKBP6 are not a common cause of non-obstructive azoospermia. Mol. Hum. Reprod. 11 (2005) 673–675.
These authors equally contributed to this paper
About this article
Cite this article
Miyamato, T., Sato, H., Yogev, L. et al. Is a genetic defect in Fkbp6 a common cause of azoospermia in humans?. Cell Mol Biol Lett 11, 557–569 (2006). https://doi.org/10.2478/s11658-006-0043-1
- Genomic imprinting