Gene responsible for lack of sperm identified

Gene variants affecting a single gene have been identified in men who do not produce sperm, giving some insight into genetic control of sperm production.

Non-obstructive azoospermia is the medical term given to a condition where no sperm are present in semen, and there is no known blockage in the ducts through which sperm are released. It is thought to affect up to ten percent of men affected by infertility, and while there a number of causes not all of them are understood. Now an international team of researchers has identified variants on a gene in four men with non-obstructive azoospermia that codes for an enzyme that helps to process a type of noncoding RNA called piRNA found only in germ cells. The findings could shed some light on how sperm are produced.

In the paper, published in The New England Journal of Medicine, the authors wrote: 'Evidence from studies in mice suggests that mutations in other piRNA enzymes are likely causes of severe spermatogenic failure in men, because disruption of multiple piRNA-related proteins leads to meiotic arrest and infertility in male mice.' They argue their findings support the theory that this mechanism is behind infertility in some humans too.

To investigate whether there is a genetic mechanism behind non-obstructive azoospermia, protein-coding regions of the genomes of 924 men with the condition were sequenced. Four unrelated men of Middle Eastern and Pakistani descent were found to have different mutations of the PNLDC1 gene. The researchers found that PNLDC1 mutations lowered the expression of piRNA processing proteins. piRNA are short strands of RNA, just 21 to 35 nucleotide in length that are found exclusively in germ cells and are responsible for post-meiotic regulation of gene expression.

Analysis of testicular tissue showed spermatogenic arrest (in which sperm fail to develop) and errors in meiosis in men with variants of this gene, with cells not developing past an immature stage of cell development. The authors suggest that faulty piRNA processing negatively affects sperm production in adult men leading to infertility, and that other genes also involved piRNA processing could lead to azoospermia.

The results of this study could help to uncover the causes of non-obstructive azoospermia, assist with diagnosis and treatment, and contribute to the development of new male contraception methods.