The connection between the father’s age at conception and germline mutations that can lead to birth defects is more complex than previously thought. Previously, it was assumed that the older a man was, the more likely he was to develop a mutation that would lead to malformations. Researchers from Linz now show in the journal “Genome Biology and Evolution” that even young men can have potentially pathogenic mutations in their sperm.
Mutations that can lead 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 dogma used to be that the older a man who wants to have children, the greater the probability of finding such a mutation in his sperm – with potentially pathogenic effects on the offspring,” explained Irene Tiemann-Boege from the university’s Institute of Biophysics Linz to the APA. Such mutations are often associated with a change in gene function and can lead to bone and heart malformations such as achondroplasia (short stature) or neurodevelopmental disorders such as autism in children.
New realization
For their study, Tiemann-Boege’s team analyzed sperm samples from anonymous donors from the fertility clinic at the 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 known cancer-causing gene (oncogene) that is highly expressed in the male gonads. It is responsible for fibroblast growth factor receptor 3 – a protein found in human tissues such as cartilage, brain, intestines and kidneys. “Even individual changes in letters of this gene can influence the functionality of the protein – with serious consequences such as various types of dysplasia,” explained Tiemann-Boege.
“We found that certain mutations in the same gene occur in different ways.” These are mutations whose frequency increases with age in testes and sperm, and mutations that arise before the male germline becomes sexually mature and are already there regardless of the man’s age and whose number remains constant with age. This is a “new insight for this type of mutagenesis”.
There is a connection with age for certain variants
The scientists examined how the mutation frequency changes with age and whether mutations spread in the stem cells of the germinal epithelium of the testis, which are responsible for the continuous production of sperm (spermatogonia), because the mutated receptor molecules result in an increased cell division rate have. They also checked whether there are functional effects of these mutations, some of which have not yet been described.
The FGFR3 variant associated with achondroplasia was found to increase with paternal age, as did another variant associated with a typically fatal skeletal disorder in children (thanatophoric dysplasia). In contrast, other FGFR3 variants would not be related to the father’s age.
“What we also saw is that some of the mutations analyzed can also occur in young test subjects,” said Tiemann-Boege. In the testes of young men they would remain small and would not form large clusters as in older subjects. But nine of the ten mutation variants would also have a functional effect and would lead to hyperactivation of the protein, as biophysical measurements showed.
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 malformations or disorders in the offspring increases.
ePaper
Read the ePaper now!
Read the daily ePaper edition of the OÖNachrichten – browse through it digitally now!
to the e-paper
info By clicking on the icon you can add the keyword to your topics.
info By clicking on the icon you open your “my topics” page. You have saved 15 tags and need to remove tags.
info By clicking on the icon you can remove the keyword from your topics.
Add the topic to your topics.