Vrije Universiteit Brussel

HOME

Genetics of male infertility

Principal Investigator: Willy Lissens Post-doctoral researcher: Katrien Stouffs

Introduction

A male factor is (co-)responsible in about half of the couples suffering from infertility problems. Two main categories of disorders can be distinguished: acquired and congenital. The last category can either be of genetic origin or can be due to a developmental disorder. We are especially interested in men with a genetic cause of male infertility. For infertile men for whom sperm cells can be retrieved either from the ejaculate or by testicular sperm extraction, in vitro fertilization, possibly with intracytoplasmic sperm injection (ICSI) might be a solution for their fertility problems. As a consequence, also potential genetic causes of infertility can be transmitted. Therefore, it is important to identify and study these genetic causes in order to be able to adequately counsel the couples.

The general aims of our studies are:

• To detect changes in the genome that are related to male infertility.
• To get more insight into the underlying mechanism and consequences of known causes of male infertility.
• To study genes expressed in testicular tissues, and therefore potentially involved in spermatogenesis.

Results

Until recently, the main focuses of studies from our centre and worldwide were deletions on the long arm of the Y chromosome and mutation studies in candidate infertility genes. Nowadays, it is obvious that a deletion of one or more azoospermia factor (AZF) regions on the Y chromosome are causing fertility problems. The consequences of partial AZFc deletions, however, are less clear since these deletions can be found in men with azoospermia or severe oligozoospermia as well as in normozoospermic men.

Although multiple studies have investigated the importance and the role of the genes located in the AZF regions, it remains doubtful which specific genes are causing fertility problems when absent due to a partial or complete AZF deletion. In our centre, three of these genes, PRY, DBY and USP9Y, have been investigated. Possibly only a combination of deleted genes might explain the fertility problems. The presence of multiple copies of most of the genes complicates the study of them.

The importance of mutations in spermatogenesis-related genes remains less understood. Several studies looking for the presence of mutations in these genes have already been published. In our centre, special attention was paid to genes located on the X chromosome. This chromosome is interesting for the study of male infertility since men only have a single copy of this sex chromosome. As a consequence, mutations in genes crucial for spermatogenesis will have an immediate impact on sperm production. Over the years it became obvious that changes in the DNA sequence of spermatogenesis genes of infertile men are rarely detected. Furthermore, most of the observed alterations are also present in normal control groups, questioning a direct relationship with the fertility problems in the studied patients. As a consequence, the underlying causes of male infertility remains largely unknown. Until now, most studies were performed at the level of individual genes.

Although genes can be thoroughly studied by mutation studies, this also poses some limitations. A first restriction is the selection of individual genes, which is mostly based on the study of genes in the mouse. Potentially also other, less known genes are essential for spermatogenesis, and alterations in these genes might cause fertility problems as well. Until the introduction of ICSI, mutations causing male fertility problems were not transmitted through males. As a consequence, it is unlikely that these mutations are widely spread throughout the population. It is thus expected that multiple mutations in different genes are responsible for the infertility, rather than that one and the same mutation will explain all fertility problems. Furthermore, the consequences of a number of mutations might be different or less severe in humans than predicted from knock-out mice models. Besides these factors that hamper the study of male infertility, one should also take into consideration that the cause of the fertility problems of possibly a (major?) part of the patients will be multifactorial.

Current and future research

In current and future studies, we will try to circumvent these limitations. First, a more global genome analysis will be used to check whether also small deletions, duplications, ... are responsible for the fertility problems in selected patient groups. By using array-comparative genome hybridization (array-CGH) analysis, we are not restricted to our own limited selection of genes. Abnormal patterns will be further investigated in more detail by analyzing more patients and controls, and by investigating the consequences of the observed abnormalities at the functional level. A second point of attention will be the examination of 'less known genes'. Several genes are described in Genbank as being expressed specifically in testis, but further information is lacking. Therefore, these genes might be important or even essential for spermatogenesis. We will try to get more insight into the exact expression pattern and function of these genes, and their possible role in male infertility.

Publications

Lissens W (1999) Genetics of male reproductive dysfunction. In: Fauser BCJM, Rutherford AJ, Strauss III JF, Van Steirteghem A (Eds.) Molecular biology in reproductive medicine. The Parthenon Publishing Group, London - New York, 479-504 (first edition; Chapter 23). Second revised edition in 2003. Lissens W (2003) Genetics of male reproductive dysfunction. In: Fauser BCJM, Bouchard P, Hsueh AJW, Rutherford AJ, Simpson JL, Strauss III JF, Van Steirteghem A (Eds.) Reproductive Medicine: molecular, cellular and genetic fundamentals. The Parthenon Publishing Group, London - New York, 615-630 (Chapter 34).

Van Landuyt, L., Lissens, W., Stouffs, K., Tournaye, H., Liebaers, I. and Van Steirteghem, A. (2000) Validation of a simple Yq deletion screening programme in an ICSI candidate population. Mol. Hum. Reprod., 6, 291-297.

Liebaers I, Van Steirteghem A, Lissens W (2001) Severe male factor: genetic consequences and recommendations for genetic testing. In: Gardner DK, Weissman A, Howles CM, Shoham Z (Eds.) Textbook of Assisted Reproductive Techniques. Laboratory and Clinical Perspectives. Martin Dunitz Ltd, London, 285-296.

Stouffs, K., Lissens, W., Van Landuyt, L., Tournaye, H., Van Steirteghem, A. and Liebaers, I. (2001) Characterization of the genomic organization, localization and expression of four PRY genes (PRY1, PRY2, PRY3 and PRY4). Mol. Hum. Reprod., 7, 603-610.

Van Landuyt, L., Lissens, W., Stouffs, K., Tournaye, H., Liebaers, I. and Van Steirteghem, A. (2001) The role of USP9Y and DBY in infertile patients with severely impaired spermatogenesis. Mol. Hum. Reprod., 7, 691-693.

Lissens W, Liebaers I, Van Steirteghem A (2002) Male infertility. In: Rimoin DL, Connor JM, Pyeritz RE, Korf BR (Eds.) Emery and Rimoin's principles and practice of medical genetics. Fourth edition. Churchill Livingstone, London, 961-981 (Chapter 36). Revised Fifth edition in 2007. Lissens W, Liebaers I, Van Steirteghem A (2007) Male infertility. In: Rimoin DL, Connor JM, Pyeritz RE, Korf BR (Eds.) Emery and Rimoin’s principles and practice of medical genetics. Churchill Livingstone Elsevier, Philadelphia (USA), 856-874 (Chapter 41).

Stouffs, K., Lissens, W., Verheyen, G., Van Landuyt, L., Goossens, A., Tournaye, H., Van Steirteghem, A. and Liebaers, I. (2004) Expression pattern of the Y-linked PRY gene suggests a function in apoptosis but not in spermatogenesis. Mol. Hum. Reprod., 10, 15-21.

Stouffs, K., Lissens, W., Tournaye, H., Van Steirteghem, A. and Liebaers, I. (2005) Possible role of USP26 in patients with severely impaired spermatogenesis. Eur. J. Hum. Genet., 13, 336-340.

Stouffs, K., Lissens, W., Tournaye, H., Van Steirteghem, A. and Liebaers, I. (2005) The choice and outcome of the fertility treatment of 38 couples in whom the male partner has a Yq microdeletion. Hum. Reprod., 20,1887-1896.

Stouffs, K., Lissens, W., Tournaye, H., Van Steirteghem, A. and Liebaers, I. (2005) SYCP3 mutations are uncommon in patients with azoospermia. Fertil. Steril., 84, 1019-1020.

Stouffs, K., Willems, A., Lissens, W., Tournaye, H., Van Steirteghem, A. and Liebaers, I. (2006) The role of the testis-specific gene TAF7L in the etiology of male infertility. Mol. Hum. Reprod., 12, 263-267.

Stouffs, K., Lissens, W., Tournaye, H., Van Steirteghem, A. and Liebaers (2006) Alterations of the USP26 gene in Caucasian men. Int. J. Androl., 29, 614-617.

Stouffs, K., Tournaye, H., Van der Elst, J., Liebaers, I. and Lissens, W. (2008) Is there a role for NXF2 in male infertility? Fertil. Steril., 90, 1787-1791.

Stouffs, K., Tournaye, H., Van der Elst, J., Haentjens, P., Liebaers, I. and Lissens, W. (2008) Do we need to search for gr/gr deletions in infertile men in a clinical setting? Hum. Reprod., 23, 1193-1199.

Stouffs, K., Tournaye, Liebaers, I. and Lissens, W (2009) Male infertility and the involvement of the X chromosome. Hum Reprod Update – In Press.

Back to top