The new mutations that affect genes and cause numerous genetic diseases are transmitted, predominantly, through the father. There is more. The danger increases with age, since the germ stem cells that give rise to spermatozoa (spermatogonia), and that contain such mutations – the latter would be responsible for the hyperactivation of an intracellular signaling pathway, known as Mapk (Mitogen-activated protein kinase) and usually activated in response to the stimulation of growth factors as frequently occurs in numerous oncological pathologies – replicate throughout life, thus increasing the probability that they will progressively increase in number.
Furthermore, cells carrying the mutated gene may present a “clonal proliferative advantage” (in practice, they replicate faster than healthy cells, increasing in number and increasing the risk of transmitting a rare disease to their children). This had already been anticipated in 2019 by research visible in the scientific journal Nature Communications and now a new molecular mechanism underlying this process is confirmed by a joint study – published in the scientific monthly The American Journal of Human Genetics – of the Bambino Gesù children’s hospital in Rome and the University of Oxford.
Paternal role
As Marco Tartaglia, head of the Molecular Genetics and Functional Genomics Unit at the Hospital, describes to Today.it, “many genetic diseases are caused by point mutations that affect single genes. These mutations can be inherited from one or both parents or arise as a “somatic” event – therefore, without being hereditary – when they appear spontaneously during the DNA replication process directly in the cells during embryonic development”. In turn, the professor explains, inherited mutations can come from the genetic makeup of the father or mother (or both) or arise de novo in the paternal or maternal stem cells (from which, respectively, mature spermatozoa and oocytes derive).
“In this case – continues Tartaglia – it is one of the two parents (most frequently the father) who transmits the mutated gene that causes the disease in the unborn child, even though the mutation does not refer to the original genetic makeup of the couple”. Then the head of the Molecular Genetics and Functional Genomics Unit of the Bambino Gesù hospital, specifies: “We are talking about probabilistic trends that have a linearity in the association. Thus, the older the future father is, the more likely it is that in the genome of the spermatozoon that fertilized the egg there may be one or more mutations. Of course, many of them are harmless, but some affect genes that are important for embryonic development and for physiological processes in general and can cause a pathology”.
Myhre Syndrome
The international multicenter study was performed by analyzing samples from 18 patients (and their families) diagnosed with Myhre syndrome, a rare genetic disorder caused by mutations in the gene “SMAD4” that arise de novo in spermatogonia, causing growth retardation, cognitive deficits, muscle hypertrophy, deafness and skeletal abnormalities. A different class of mutations in this same gene is known to cause juvenile gastrointestinal polyposis, a rare disease characterized by juvenile hamartomatous polyps in the gastrointestinal tract with risk of tumor degeneration.
However, those affected by Myhre syndrome do not have a higher risk of developing tumors than the normal population. The demographic data of 35 families of American patients affected by the same disease were also analyzed. Well, the research team has shown that the mutations that cause this disease always have a paternal origin.
Researchers at the MRC Weatherall Institute of Molecular Medicine (University of Oxford) then highlighted how these mutations grant a proliferative advantage to germ stem cells by establishing their clonal expansion. This increased cell division represents a process in some ways similar to that which occurs in cancer cells – “even in neoplasms, in fact, we have cells that divide much more than normal cells”, Tartaglia points out – and increases the possibility that a spermatozoon determines a mutation that causes the pathology. “The study demonstrates the presence of clonal expansion in association with mutations that affect a protein that operates outside the signaling pathway already associated with this phenomenon”, the professor continues.
“This discovery – Tartaglia further admits – indicates that, as paternal age increases, more molecular mechanisms can contribute to increasing the probability of transmission to the unborn child of a mutated gene potentially causing disease”. He concludes: “We are talking about important results both for the relevant implications in the field of genetic counseling and calculation of reproductive risk, and in terms of new knowledge”.