Gene Mutations Associated with Male Infertility

Infertility is a complex medical problem for several reasons. It is very frequent, since about 15% of couples worldwide fail to conceive, the male factor being involved in roughly 50% of cases. Secondly, the background of male infertility seems extremely heterogeneous including many environmental causes. Thirdly, in as many as 30% of individuals, the origin of infertility remains unknown (Poongothai et al., 2009). Chromosomal aberrations involving an abnormal number or structure of sex chromosomes or autosomes are found in approximately 5% of infertile men (for review see Ferlin et al., 2007). These aberrations often result in congenital syndromes, male infertility being one of their numerous features. Among them, Klinefelter syndrome is relatively common. It is caused by the presence of an extra X chromosome, 47,XXY. Another example is the 46,XX male syndrome. In a majority of cases, it results from translocation of a Y chromosome segment, containing the SRY gene, on the X chromosome. Structural aberrations of autosomes are much more frequent in males with isolated infertility than in the general population. For instance, Robertsonian translocation is 9-fold more frequent in infertile patients than in the general population. The most common Robertsonian translocation associated with male infertility is the one originating from chromosomes 13 and 14. Also reciprocal translocations are more frequent (4-10-fold) in infertile than in fertile males (for review see O’Flyn O’Brien et al., 2010). In the recent years much attention has been paid to mutations causing male infertility. These mutations were identified in genes known to be responsible for male germ cell development or, for other male reproductive processes. Thousands of genes in these categories are expressed in human testes and any of them can potentially cause infertility when mutated. This circumstance makes studies on genetic causes of male infertility extremely complex. Therefore, the generation of about 400 mouse models of male infertility in recent years has been very helpful to select the best human candidates for mutation screening in infertile men. These models represent defects at different steps of sperm cell development (Matzuk & Lamb, 2008). In fact, several hundred mutations have been identified in men suffering reproductive defects and by analogy with the mouse model, these mutations might affect human male reproduction. Also, state of the art technologies, such as genome-wide scanning, currently provide an enormous amount of new mutation records. Unexpectedly, this large amount of data on genetic variation contrasts with a very low number of reports describing well documented causative male infertility mutations. This is due to multiple obstacles in collecting additional necessary data. One of the major difficulties is