Children with older father risk to develop malformations

(Stem Cells News image)

Researchers now recognize that older age in a father can increase the risk that his children will develop a variety of disorders, including autism, schizophrenia, even a common form of dwarfism. The question is, how?

Now, in Stem Cell Reports, a research team has solved the problem for one such disease, Apert syndrome, and says its findings may extend to other paternal age-associated disorders. It is testing those disorders to see if that is true.

Scientists have for some time believed that the mutation for Apert syndrome — in which children are born with a disfigured skull, face, hands and feet — first occurs in the healthy fathers’ spermatogonial stem cells, the male germ stem cells that produce sperm. Building on that hypothesis, the Weill Cornell investigators provide evidence to support the idea that as a man ages, the number of germ stem cells with this mutation increases, crowding out normal stem cells in the testicle. Their increasing proportion leads to a greater chance of a mutated sperm fertilizing an egg than in a younger man with relatively fewer mutated cells.

Although Apert syndrome is a rare disease, risk “increases considerably when a man is in his late 30s and exponentially thereafter due to production of a greater proportion of mutated sperm,” says the study’s senior investigator Dr. Marco Seandel, assistant professor of cell and developmental biology in surgery at Weill Cornell.

The findings prove that at least in this disorder, there is truth to the “selfish selection” hypothesis that proposes that when mutated stem cells compete with normal stem cells, the abnormal cells prevail, Dr. Seandel says. Scientists have proposed the theory to explain the effects of paternal age on children’s health.

The findings prove that at least in this disorder, there is truth to the “selfish selection” hypothesis that proposes that when mutated stem cells compete with normal stem cells, the abnormal cells prevail, Dr. Seandel says. Scientists have proposed the theory to explain the effects of paternal age on children’s health.

“There had been no experimental proof for this hypothesis, but here we show that the Apert syndrome mutation makes male germ stem cells more competitive, and they go about replacing their normal counterparts,” he says. “They seem to be turning on growth pathways that preferentially produce new stem cells with this mutation. The balance of stem cells shifts from normal to mutated.”

Scientists have only recently understood that as men age, they produce more genetic abnormalities that can be passed on to their children, Dr. Seandel says. One example is the type of mutation in genes in which a single nucleotide — a “letter” in the genetic code — has been changed. These “point mutations” can lead to disorders or can contribute to susceptibility to disease, he says.

“The older the father is when a child is conceived, the more point mutations he passes on to that child. By contrast, the number of point mutations a child inherits from the mother appears to be relatively fixed — it does not change no matter how old the mother is,” Dr. Seandel says. Older women, however, contribute other kinds of genetic defects, such as chromosomal abnormalities, he adds.

As more is known about the paternal age effect, a question arises as to what a man should do to protect his future children, Dr. Seandel says.

“The number of children born to older fathers is rising rapidly, and if the paternal age effect is as widespread as we think it might be, one solution for men who plan to delay having children is to consider banking their sperm,” he says.

from:weill.cornell.edu/news/news/2014/07/older-fathers-produce-mutated-germ-cells-that-crowd-out-normal-stem-cells-marco-seandel.html

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