Discovery gives better understanding of Down’s syndrome

A new discovery may have identified a gene responsible for the cause of an abnormal number of chromosomes, known as aneuploidy, sometimes found in humans.  Aneuploidy is the underlying cause of many genetic disorders in humans, including Down’s syndrome, and is a principle cause of pregnancy loss.

The study on mice by researchers at U.S. Department of Energy’s Lawrence Berkeley National Laboratory and the University of Tennessee, Knoxville found that if the mother’s egg cell has one copy of a mutation in the gene Bub1 then she will produce much fewer live offspring.

Normally both copies of a gene must have the mutation for it to have a detrimental effect on the organism.  It is very unusual to have a mutation in both copies of a gene and the healthy gene will override the mutated copy, but this is not the case for Bub1 which makes this finding significant.

“We found that a mutation in a single copy of the Bub1 gene can have an impact — and this is not the case with most genes. With Bub1, if you have one bad gene and one healthy gene, there’s a problem,” says Francesco Marchetti of Berkeley Lab’s Life Sciences Division, part of the team who made this discovery.

Bub1 plays a central role during the cell division process meiosis, which facilitates the transformation of a stem cell to an egg.  Bub1 is involved in part of the control mechanism that ensures chromosomes divide correctly, but a mutation in Bub1 causes an error at this point which can result in an egg with one extra chromosome or a missing chromosome.  Mutations like this in humans greatly decrease the chances of the embryo surviving, or lead to offspring with genetic disorders.  Down’s syndrome, also known as trisomy 21, is the result of an extra chromosome on chromosome 21.  It occurs in about 1 in 1400 births when the mother is in her early 20’s with this figure increasing to 1 in 25 if the mother is over 45.

The risk of aneuploidy due to a mutation in Bub1 is female specific.  When a male with one bad copy of the gene mated with a normal female the number of offspring produced was not affected, but a normal male mating with a female carrying one bad copy of the gene produced very few offspring.  This is because aneuploidy is generated in the egg, then passed on to the zygote that forms when a sperm fertilizes the egg.  The team also found that the chance of a Bub1 mutation causing an abnormal number of chromosomes in the zygote increases with age.

Although the research was carried out on mice, it may help us explain how and why aneuploidy occurs in humans, and why the risk of genetic disorders in children increases with the mother’s age.

These results were published in the July 13-17 2009 online early edition of the Proceedings of the National Academy of Science.