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Association of Meiotic Arrest with Lack of BOULE Protein Expression in Infertile Men

Institute of Reproductive Medicine (C.M.L., A.K., E.N., J.G.), Westphalian Wilhelms-University, D-48129 Muenster, Germany; and Departments of Obstetrics, Gynecology, and Reproductive Sciences, Physiology, and Urology (E.Y.X., R.A.R.P.), Program in Development and Stem Cell Biology, University of California, San Francisco, California 94143-0556

Address all correspondence and requests for reprints to: Prof. Dr. J. Gromoll, Institute for Reproductive Medicine, Domagkstrasse 11, D-48149 Münster, Germany. E-mail: gromolj{at}uni-muenster.de.

Spermatogenesis is a complex developmental process of mitotic and meiotic cell divisions that ultimately results in production of haploid spermatozoa. Recent studies in flies demonstrate that the BOULE gene encodes a key factor of meiosis in male germ cells, regulating the expression of twine, a cdc25 phosphatase, which promotes progression through meiosis. In this study, we investigated whether a common mechanism underlies the block of germ cell maturation observed in idiopathic and nonidiopathic azoospermic patients with meiotic arrest. We examined, by immunohistochemistry, BOULE and CDC25A phosphatase protein, the human homolog of twine, expression in 47 men with meiotic arrest, mixed atrophy, or normal spermatogenesis. The presence of genetic alterations within the BOULE gene was investigated by single-stranded conformation polymorphism. BOULE protein expression in men with complete spermatogenesis can be restricted to stages from leptotene up to stages of late spermatocytes, whereas CDC25A expression ranges from leptotene spermatocytes to elongating spermatids. Although spermatocytes were present in all testicular biopsies with meiotic arrest (28 testes), BOULE protein expression was completely lacking. In addition, in nearly all biopsies in which BOULE was absent, CDC25A was concomitantly lacking. However, no mutations or polymorphisms in the BOULE gene were identified, which could explain the lack of BOULE or CDC25A expression. These results indicate that a major group of infertile men with meiotic arrest lack BOULE protein and its putative target, CDC25A expression. The spermatogenic failure seems to arise from factor(s) upstream of BOULE, which are possibly involved in regulating transcription and/or translation of BOULE. Thus, the spermatogenic damage leading to meiotic arrest is independent of the etiology and indicates that BOULE is a possible fundamental mediator of meiotic transition in the human.

This work was supported by the Fritz-Thyssen and Alexander von Humboldt Foundations and by a grant of the Innovative Medical Research of the University (IMF-GR110311).

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