Genetic Flaw May Explain Rare Form of Male Infertility

Researchers have identified a gene mutation that appears to inhibit sperm formation, leading to a cause of failed sperm production.

With Ramesh Pillai, PhD, and commentary by Joshua D. Safer, MD

The gene mutation, TDRD9, may provide an explanation for some cases of non-obstructive azoospermia, which affects 1% of all men but as many as 20% of infertile men,1 according to research appearing in the Journal of Medical Genetics, a BMJ publication.

The study conducted by a team of researchers from Israel and the United States focused on 5 infertile Bedouin men from the same extended family—with a notable history of inbreeding—all of whom had the TDRD9 mutation, which has no impact on female fertility.1

“Our study is the first to demonstrate the importance of the gene, TDRD9, known to be involved in silencing of line-1 retrotransposon in the male germ line for enabling fertility,” according to the researchers.

“This is also the first report of the participation of a member of the TDRD protein family in male fertility in humans,” they reported.

Genetic mutation discovered that leads to a rare form of male infertility.

Cause of Male Infertility Uncovered

Men with nonobstructive azoospermia have few options for treatment. Available therapies include testicular sperm extraction for men with viable sperm and hormone therapy if the cause of the infertility is hormonal. 2 However, success in achieving fertility for these patients generally is low.

In addition to hormonal causes, genetic alterations are believed to play a role in roughly 20% to 30% of cases of non-obstructive azoospermia, according to the authors of the latest study. Of these, approximately 28% are diagnosable – including mutations of the cystic fibrosis gene and known chromosomal anomalies -- which provides clinicians a chance to counsel patients and offer assisted reproduction therapies.

Of the remaining cases, as many as four in 10 are considered idiopathic, only one male was found to have traces of dead sperm, while the rest had no sperm at all, resulting from a frame shift in exon 5 of the gene, a deletion of base pairs that likely result in a shortened version of the TDRD9 protein that is a frame shift of its normal function.

Analysis of genetic material from 202 other Bedouins, nomadic peoples of the Middle East, as well as DNA samples from 31 fertile Bedouin men, failed to find the mutation. Evidence of this mutation was not found in a database search of 77 other Bedouins, suggesting that the prevalence of the defective gene is less than 1 in 620 people in that ethnic group, according to the researchers.

Having studied the TDRD9 and related genes,3 Ramesh Pillai, PhD, professor of molecular biology at the University of Geneva Department of Molecular Biology, in Switzerland said, these genes and their associated proteins play a variety of roles in cells, one of which is to produce scaffolds on which other proteins can aggregate.

In the case of spermatogenesis, the mutation appears to be depriving germ cells of an essential building block in the formation of sperm.

“It takes out an essential component of a small RNA machinery that is essential for transposon silencing. Thus, genome integrity is compromised,” Dr. Pillai told EndocrineWeb.

Too Soon for a Clinical Application

"The study is a great piece of work, a marvelous example of the power of modern investigative tools leveraged by diligent scientists like the authors of the study when they identify large families with certain medical conditions," Joshua D. Safer, MD, FACP, medical director of the Center for Transgender Medicine and Surgery at Boston Medical Center, told EndocrineWeb.

"However, I don’t think that the finding has an immediate impact on clinical medicine in that there is still no treatment for this situation," added Dr. Safer, also an associate professor of Medicine and Molecular Medicine at Boston University School of Medicine.

“Although the paper identifies a gene that causes the problem, clinically nothing has changed,” he said.

This study was partially supported by grants from the Natural Science Foundation of
China (NSFC), Israel Science Foundation, and Ben-Gurion University of the Negev, Faculty of Health Sciences. No authors indicated financial conflicts of interest.

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