Even young people with pathogenic mutations in the germline

The link between paternal age at conception and germline mutations that lead to birth defects is more complex than previously thought. Previously, it was thought that the older a man was, the more likely he was to develop a mutation that would lead to defects. Researchers from Linz now show in the journal “Genome Biology and Evolution” that even young men can carry pathogenic mutations in their sperm.

Mutations leading to congenital diseases in offspring are more common in the male germline and are orders of magnitude higher than the average mutation rate in the human genome. “The older a man who wants to have children, the more likely he is to find such a mutation in his sperm – which could have pathogenic effects on the offspring,” explained Irene Tieman-Boge from the university's Institute of Biophysics. Linz to APA. Such mutations are often associated with a change in gene function and lead to skeletal and cardiac defects such as achondroplasia (short stature) or neurodevelopmental disorders such as autism in children.

Specimens from anonymous donors

For their study, Tiemann-Pogin's team analyzed sperm samples from anonymous donors from the fertility clinic at Linz University Hospital. They examined the frequency of mutations for ten different variants of the FGFR3 gene in men aged 23 to 59 years. FGFR3 is a cancer-causing gene (oncogene) that is overexpressed in the male genitalia. It is responsible for fibroblast growth factor receptor 3 – a protein found in human tissues such as cartilage, brain, intestine and kidneys. “Even individual changes in the characters of this gene can affect the function of the protein – with severe consequences, such as various types of dysplasia,” Tieman-Boge explained.

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“We found that some mutations in the same gene occur in different ways.” These are mutations that increase in frequency with age in sperm and spermatozoa and mutations that arise before the male germline reaches sexual maturity and are already present regardless of the age of the male and their number remains constant with age. This is “new insight into this type of mutation.”

The scientists studied how the mutation frequency changes with age and whether the mutations spread to the stem cells of the germinal epithelium of the testis, which are responsible for the continued production of sperm. There is a ratio. They also tested whether these mutations have functional consequences, some of which have not yet been described.

The FGFR3 variant associated with achondroplasia was found to increase with paternal age, as well as another variant associated with a more commonly fatal skeletal disorder in children (thanatophoric dysplasia). In contrast, other FGFR3 variants were not associated with paternal age.

Mutations are even smaller in young men's sperm

“What we saw was that some of the mutations that were analyzed could also occur in young test subjects,” Tiemann-Boge said. They are smaller in the testicles of young men and do not form large clusters like in adults. But nine out of ten mutational variants have a functional effect and, as shown by biophysical measurements, lead to hyperactivity of the protein.

According to the expert, such mutations can occur very early, sometimes even before a man reaches sexual maturity. Depending on how many germline cells are affected, the risk of defects or disorders in the offspring increases.

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Service: Website: https://doi.org/10.1093/gbe/evae015

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