Human chromosome deletions in Yq11, AZF candidate genes and male infertility: history and update

Abstract

Human chromosome deletions in Yq11 seem to occur frequently as de novo mutation events in men with idiopathic azoospermia or severe oligozoospermia. However, the molecular extensions of these deletions are variable. They can be large and therefore visible under the microscope or small, not visible under the microscope, and containing the deletion of one or more DNA loci recently mapped in an apparently consecutive order along the Yq11 chromosome region. The results of 20 extensive microdeletion screening programmes have now corroborated the prevalence of the deletion of three non-overlapping DNA regions in proximal, middle and distal Yq11, which were designated earlier as AZFa, AZFb and AZFc. Deletions of single DNA loci were also reported, but as de novo and as polymorphic mutation events. Their clinical significance with regard to the men's infertility should therefore initially be handled with caution. Multiple Y genes expressed in human testis have now been mapped to each AZF region. At least one of them should be functional in human spermatogenesis and, if mutated, cause azoospermia. However, gene-specific mutations leading to the azoospermia phenotype have not yet been found for any of these AZF candidate genes. This might raise the question as to whether an AZF gene really exists in Yq11 or if the azoospermia phenotypes are only observed after deletion of a complete AZF region, after deletion of its complete gene content.

A multi-faceted approach to understanding male infertility: gene mutations, molecular defects and assisted reproductive techniques (ART)

“…The mosaic karyotype 45×/46XY is found in infertile men with an incidence of 4 % and known to cause infertility [33]. All males with discordant sex chromosomal pattern are azoospermic due to absence of long arm of the Y chromosome containing the azoospermic factor (AZF) gene, which is necessary for normal spermatogenesis [34]. Translocation of SRY gene (testisdetermining factor) from chromosome Y to chromosome X has also been reported [35].…”

“…A family of PRY genes, essential in the regulation of apoptosis is also found in the AZFb region [53]. Whereas small AZFb deletions have been related to variable testicular phenotypes [54], larger AZFb deletions and those that include genes PRY1/PRY2 seem to cause complete meiotic arrest [34]. Recently, studies have revealed that in cases where all the genes in the AZFb region excluding RBMY and PRY are deleted, patients present with hypo spermatogenesis [20].…”

“…Recently, studies have revealed that in cases where all the genes in the AZFb region excluding RBMY and PRY are deleted, patients present with hypo spermatogenesis [20]. However, if both the RBMY and PRY genes are removed, spermatogenesis is arrested completely, indicating that RBMY and PRY are the major genes involved in fertility [17,34].…”

Clinical data for 185 infertile Iranian men with Y-chromosome microdeletion

“…Several investigations have shown that 10-15 % of infertile men with azoospermia or severe oligozoospermia have small deletions of the Yq-chromosome, which are not detectable in a karyotype test [8]. A study performed on 3073 infertile men found that Yq microdeletions were detected in 5.5 % of patients who suffered from oligozoospermia and in 8.3 % of those suffering from non-obstructive azoospermia [9]. Yq microdeletions rarely occur in fertile men and men with sperm densities greater than 5×10 6 /ml.…”

Efficient combined FISH and PRINS technique for detection of DAZ microdeletion in human sperm

“…In more than 60 % of cases the origin of reduced testicular function is unknown [2,3]. Evidence exists that microdeletions of the Y chromosome play a causal role in male infertility [4]. Molecular and cytogenetic studies from infertile men have shown that microdeletions within the azoospermia factor region (AZF) [5] are prevalent causes of male factor infertility.…”