Miscarriage Gene Found for Mice

They have more failures when missing a key protein

THURSDAY, May 9, 2002 (HealthDayNews) -- The absence of a key protein significantly raises the risk in mice of miscarriages that are linked to chromosomal defects, Swedish researchers have found.

The protein, synaptonemal complex protein 3 (SCP3), is believed to help chromosomes -- the scaffolding for genes -- separate during cell division. When this process goes awry, it can lead to a catastrophic condition called aneuploidy, in which embryos contain an abnormal number of chromosomes.

Aneuploidy is the chief cause of gene-related miscarriage in people. Down syndrome, marked by a third and superfluous copy of chromosome 21, is an example of a form of the defect that more typically ends in a failed pregnancy.

Another feature of the chromosome problem is that it becomes more common with older mothers -- explaining why birth defects like Down syndrome are dramatically more likely in women over age 35.

Terry Hassold, a reproduction expert at Case Western Reserve University in Cleveland, calls the Swedish work "provocative." However, he wonders how applicable it will prove to be in people.

The researchers "clearly show there's an increase in aneuploidy in these females. But the relationship between that and maternal age-related [aneuploidy] in humans is still to be determined," Hassold says.

Christer Höög, a cell biologist at Stockholm's Karolinska Institute, led the research, which appears in tomorrow's issue of the journal Science.

Höög and his colleagues earlier showed that male mice missing SCP3 were sterile. So, experts had anxiously awaited the results of the latest experiment, Hassold says.

The researchers bred mutant female mice, missing the gene for SCP3, with fertile male animals. Although aneuploidy is typically quite rare in mice -- affecting at most a few percent of embryos -- their litter sizes fell by about a third, from 8.9 pups for genetically normal animals to 5.9 for the mutants, Höög's group found.

The rate of deadly aneuploidy rose to between 50 percent and 60 percent of embryos as the mother mice aged. Additional tests convinced the researchers the defect was disrupting chromosome assembly in egg cells rather than by other means.

"Here is a protein machinery that is required to sort and supervise this chromosome segregation process," Höög says. "By removing one of them, you get this subtle defect. It's not essential, but it makes things better."

Höög says SCP3 isn't acting alone in chromosome regulation. "I believe that if you would mutate additional proteins you might have similar effects," he says.

Dorothy Warburton, a genetics expert at Columbia University in New York City, agrees: "We can't be dealing with a mutation of a single gene that accounts for most cases" of aneuploidy in people.

Humans have the most aneuploidy of any creature studied, with as many as 20 percent to 30 percent of all conceptions affected, Warburton says. Why that's the case, and why the defect becomes more common with maternal age, "is pretty much a mystery."

One theory, Warburton adds, is that aneuploidy is evolution's brake on human reproduction, allowing for adequate spacing between births and improving the odds that offspring will survive to mate.

What To Do

To find out more about aneuploidy, try the Southern California Center for Reproductive Medicine. For more on miscarriage, try this article from the BBC.

The National Down Syndrome Society has more on that condition.

SOURCES: Christer Höög, Ph.D., professor, molecular cell biology, Karolinska Institute, Stockholm; Dorothy Warburton, Ph.D., professor, genetics and development, Columbia University, New York City; Terry Hassold, Ph.D., professor, genetics, Case Western Reserve University, Cleveland; May 10, 2002, Science
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