GREATER RATES OF MITOCHONDRIAL MUTATIONS DISCOVERED IN CHILDREN BORN TO OLDER MOTHERS
The discovery of a
"maternal age effect" by a team of Penn State scientists that could
be used to predict the accumulation of mitochondrial DNA mutations in maternal
egg cells -- and the transmission of these mutations to children -- could provide
valuable insights for genetic counseling. These mutations cause more than 200
diseases and contribute to others such as diabetes, cancer, Parkinson's
disease, and Alzheimer's disease. The study found greater rates of the
mitochondrial DNA variants in children born to older mothers, as well as in the
mothers themselves. The research will be published in the early online edition
of theProceedings
of the National Academy of Sciences on
October 13, 2014.
Mitochondria are
structures within cells that produce energy and that contain their own DNA.
"Many mitochondrial diseases affect more than one system in the human
body," said Kateryna Makova, professor of biology and one of the study's
primary investigators. "They affect organs that require a lot of energy,
including the heart, skeletal muscle, and brain. They are devastating diseases
and there is no cure, so our findings about their transmission are very
important."
The multidisciplinary
research team set out to learn whether maternal age is important in the
accumulation of mitochondrial DNA (mtDNA) mutations, both in the mother and in
the child as a result of transmission. Collaborating with Ian Paul,
a pediatrician at the Penn State Milton S. Hershey Medical Center, they took
samples of blood and of cells inside the cheek from 39 healthy mother-child
pairs. Because mtDNA is inherited only maternally, paternal mtDNA was not a
factor in the study. Studying healthy individuals gave the researchers a
baseline for future studies of disease-causing mutations.
Through DNA
sequencing, they found more mutations in blood and cheek cells in the older
mothers in the study. Maternal age of study participants ranged from 25 to 59.
"This finding is not surprising," Makova said, "because as we
age, cells keep dividing, and therefore we will have more mutant genes."
But finding greater rates of mutations in children born to the older mothers
did come as a surprise. The researchers believe a similar mutation process is
occurring both in the cells of the mothers' bodies and in their germ lines.
The study led to
another important discovery about egg-cell development. Although it was known
that developing egg cells go through a "bottleneck" period that
decreases the number of mtDNA molecules, scientists didn't know how small or
large this bottleneck is. "If the bottleneck is large, the genetic makeup
of the mother's mitochondria will be passed to her children," Makova
explained. "However, if it is tiny -- if there is a severe decrease in
mitochondrial molecules during the egg-cell development -- then the genetic
makeup of the child might differ dramatically from that of the mother. What we
discovered is that this bottleneck is indeed very small."
This finding is
especially important for mothers who have a mitochondrial disease. For many
mitochondrial diseases, 70 to 80 percent of molecules need to have the
disease-causing variant for the disease to manifest itself. But for others,
only 10 percent of the mtDNA molecules with the variant are needed to cause
disease. "If the bottleneck is very small, as we've found in our study,
these percentages can change dramatically," Makova said. "Knowing the
size of the bottleneck allows us to predict, within a range, the percentage of
disease-carrying molecules that will be passed on to the child."
Knowledge about both
the maternal age effect and the bottleneck size is useful in family planning.
"We have some predictive power now and can assist genetic counselors in
advising couples about the chances of mitochondrial diseases being passed to the
next generation," Makova said. "Everyone is concerned about Down
syndrome because that is a common genetic problem. We have now added another
set of genetic disorders that also might be affected by the age of the mother.
It is good for couples to have this knowledge as they make family-planning
decisions."
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