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Hum. Reprod. Advance Access published online on June 10, 2008
Human Reproduction, doi:10.1093/humrep/den191
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© The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Polymorphisms in the human cysteine-rich secretory protein 2 (CRISP2) gene in Australian men

D. Jamsai1,2, A. Reilly3, S.J. Smith1,2, G.M. Gibbs1, H.W.G. Baker4, R.I. McLachlan3, D.M. de Kretser1,2 and M.K. O'Bryan1,2,5

1 Centre for Reproduction and Development, Monash Institute of Medical Research, Monash University, Clayton, VIC, Australia 2 The Australian Research Council Centre of Excellence for Biotechnology and Development, Monash University, Clayton, VIC, Australia 3 Prince Henry's Institute, Monash Medical Centre, Clayton, VIC, Australia 4 Department of Obstetrics and Gynaecology, University of Melbourne, Carlton, VIC, Australia

5 Correspondence address. Tel +61-3-95947407; Fax: +61-3-95947439; E-mail: moira.obryan{at}med.monash.edu.au

BACKGROUND: Cysteine-rich secretory protein 2 (CRISP2) is localized to the human sperm acrosome and tail. It can regulate ryanodine receptors Ca2+ gating and binds to mitogen-activated protein kinase kinase kinase 11 in the acrosome and gametogenetin 1 (GGN1) in the tail.

METHODS AND RESULTS: In order to test the hypothesis that CRISP2 variations contribute to male infertility, we screened coding and flanking intronic regions in 92 infertile men with asthenozoo- and/or teratozoospermia and 176 control men using denaturing HPLC and sequencing. There were 21 polymorphisms identified, including 13 unreported variations. Three SNPs resulted in amino acid substitutions: L59V, M176I and C196R. All were only present in a heterozygous state and found in fertile men. However, the C196R polymorphism was of particular interest as it resulted in the loss of a strictly conserved cysteine involved in intramolecular disulphide bonding. Screening of an additional 637 infertile men identified 23 heterozygous C196R men to give an overall frequency of 3.6%, compared with 3.4% in control men. The functional significance of the C196R polymorphism was defined using a yeast two-hybrid assay. The C196R substitution resulted in the loss of CRISP2–GGN1 binding.

CONCLUSIONS: Although none of the many polymorphisms identified herein showed a significant association with male infertility, functional studies suggested that the C196R polymorphism may compromise CRISP2 function.

Key words: CRISP2/TPX1/GGN/male infertility/single-nucleotide polymorphism

Submitted on October 10, 2007; resubmitted on March 25, 2008; accepted on April 16, 2008.


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