Genetics and stem cells

Gene linked to low sperm count

“A faulty gene could help to explain some cases of unexplained male infertility,” reported BBC News.

The story is based on research that tested the DNA of men with unexplained low sperm counts. The study specifically looked for mutations in the gene coding for the NR5A1 protein, which helps regulate the production of a number of other proteins involved in the development of sperm and genitals. The researchers found that 7 out 315 infertile men tested possessed a mutated form of the gene. This mutation was found to change the way NR5A1 regulated the production of certain proteins.

This research has identified a potential genetic cause of fertility problems in a very small proportion of men (only 4% of those tested had the mutation). Larger studies are now needed to accurately assess the proportion of men with the mutation and precisely how it impairs sperm development.

Although the men studied had low sperm counts, problems conceiving can be due to a wide variety of causes in either or both partners, and often no cause can be identified.

Where did the story come from?

The study was carried out by researchers from the Institut Pasteur in France. It was funded by grants from a number of scientific foundations, including the Institut des Maladies Rares, a government-funded French medical institute.

The study was published in the peer-reviewed American Journal of Human Genetics.

This research was covered accurately by the BBC.

What kind of research was this?

This case-control study tested whether men seeking infertility treatment for unexplained reduced sperm counts had genetic mutations in a gene called NR5A1. The NR5A1 gene normally contains the genetic code for producing a “nuclear receptor protein” in the testes. This receptor protein is involved in regulating genes that help control the male hormones involved in producing sperm.

The researchers say that mutations in the NR5A1 gene have previously been associated with significant genital abnormalities and more severe developmental abnormalities of the testes and ovaries.

What did the research involve?

The study recruited 315 French men who had unexplained reduced sperm counts and who sought infertility treatment. The study excluded men with known causes of infertility, such as abnormalities in their chromosomes, or whose occupations or lifestyles are known to reduce fertility. The men were of mixed ancestry and were representative of the local Parisian population. These men formed the case group.

To provide a control group, the researchers used DNA from a library containing 1,064 samples from 52 worldwide populations, plus additional DNA samples from 140 French men, 89 men of West African origin and 96 men of North African origin. However, although these men were healthy, their fertility and semen quality was unknown.

The researchers then assessed the genetic sequence of the NR5A1 gene in both these sets of men. To test the effects of any mutations identified in this gene, the researchers genetically modified cells in the laboratory to contain the mutated form of the gene. They then observed how the mutation affected the function of the protein that the gene was responsible for producing in the cells.

What were the basic results?

Out of the 315 men who had unexplained reduced sperm counts, seven men had mutations of the NR5A1 gene. Six of the seven men had severe failure to produce sperm, and one man’s sperm production was moderately affected. None of the 2,100 controls had mutations in this gene.

The researchers had hormone data for four of the men with the mutation. Testosterone levels were low in two of the men and inhibin B, a protein involved in regulating the development of sperm, was low in all four men. The men also had normal to elevated levels of two hormones involved in reproduction, called luteinizing hormone and follicle-stimulating hormone.

When the researchers engineered cells to carry the mutated gene, they found that the protein produced by mutant NR5A1 was in the appropriate location of the cell (the nucleus), but its function (controlling the activation of genes) was impaired.

How did the researchers interpret the results?

The researchers say that mutations in NR5A1 are associated with unexplained, severe failures in sperm production in otherwise healthy men. They estimate that approximately 4% of men with such unexplained low sperm counts may have a mutation in this gene.

The researchers say that their experiments using cell culture show that mutations in this gene may lead to a “functional disturbance of the NR5A1 protein”, which may affect the subsequent regulation of genes that is normally seen during the development and functioning of the testes and ovaries.


This small case-control study found that mutations of the NR5A1 gene were present in 4% of 315 men with otherwise unexplained reduced sperm counts.

This study suggests a potential cause of poor sperm production in a very small proportion of men for whom the cause is otherwise unclear. The study’s small size means the prevalence of NR5A1 mutations among men with fertility problems may be higher or lower than the 4% suggested by the study’s authors.

Additionally, as the study excluded men who had known causes of infertility, it does not give an indication of how common the gene is in the overall population of men who visit their doctor with fertility problems. The study looked at the hormone levels in only four men with mutations to this gene. Further research is needed to assess how this genetic mutation affects hormone regulation and sperm production in a larger sample of men.

Overall, this study has made a useful contribution to understanding one potential cause of reduced sperm count in men. However, this research provides only a small clue to male infertility, not the complete answer. Problems conceiving can have a wide variety of causes in either or both partners, and often no cause is identified. This research assessed a small number of men with low sperm count, but low numbers of sperm may not be a causative or contributory factor in all men with fertility problems. Structural or motility problems of the sperm or blockage of the tubes that store and transport sperm are also common causes.

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