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A new genetic mechanism for severe forms of male infertility

Newcastle University scientists have identified a new genetic mechanism that can cause severe forms of male infertility. This breakthrough could help develop better treatment options for patients in the future.

Male infertility

Approximately half of all cases of infertility are the result of male infertility. It affects around 7% of the male population. In most cases, the cause is unknown. While genetics is known to play a role in male infertility, there currently is a lack of diagnostically relevant genes. In addition, at least 40% of cases are classed as idiopathic.

De novo mutations (DNMs) have been found in previous studies to play a role in other conditions with reproductive lethality, such as neurodevelopmental disorders. There are also cases of male infertility where de novo chromosomal abnormalities play a role, such as an additional X chromosome resulting in Klinefelter syndrome. Altogether, these de novo events explain up to 25% of all cases of nonobstructive azoospermia (failure of spermatogenesis). However, to date, a systematic analysis of the role of DNMs in male infertility has yet to be conducted.

The role of DNMs

In a recent study, published in Nature Communications, researchers analysed exome sequencing data of 185 infertile males and their unaffected parents to explore the role of DNMs in severe male infertility.

From their analysis, the team found 145 rare protein-altering mutations that were likely to negatively impact male infertility. Out of these, 29 affected genes are directly involved in processes linked to spermatogenesis or reproduction. One promising candidate gene was the mRNA splicing gene, RBM5, which is an essential regulator of male germ cell pre-mRNA splicing. This gene has been previously implicated in male infertility in mice.

In a follow-up study, the researchers identified six rare pathogenic missense mutations affecting this gene in a cohort of 2,506 infertile male. They found no such mutations in a cohort of 5,784 fertile men.

Overall, this study provides evidence for the role of DNMs in severe male infertility and highlights potential new candidate genes affecting fertility. The team hope now to expand their work by studying thousands of patients and their parents in a large international consortium. They will also further explore the effects of these newly identified mutated genes on spermatogenesis and overall fertility.

Image credit: canva

More on these topics

Fertility / Genetic Variants / Sperm