Link between missing DNA, birth defects confirmed

In 2010, scientists in Italy reported that a woman and her daughter showed a puzzling array of disabilities, including epilepsy and cleft palate. The mother had previously lost a 15-day-old son to respiratory failure, and the research team noted that the mother and daughter were missing a large chunk of DNA on their X chromosome. But the researchers were unable to definitively show that the problems were tied to that genetic deletion.

Now a team from the University of Pennsylvania and The Children's Hospital of Philadelphia has confirmed that those patients' ailments resulted from the genetic anomaly. Creating mice that lacked the same region of DNA, the Penn and CHOP researchers showed that these animals suffered the same problems that afflicted the mother, daughter and son -- cleft palate, epilepsy and respiratory difficulties, a condition called human Xq22.1 deletion syndrome. And, by clarifying the syndrome's genetic basis, the researchers have laid the foundation for identifying the underlying molecular mechanism of these troubles and potentially treating them at their biological root.

"This study has demonstrated that deleting this region in mice causes them to respond like humans with the same deletion," said P. Jeremy Wang, senior author on the study and professor in the Penn School of Veterinary Medicine's Department of Animal Biology. "Now that we have a mouse model, we can dissect and try to genetically pinpoint which genes are responsible."

Wang co-led the study with his postdoctoral researcher Jian Zhou. Additional coauthors included Penn Vet's N. Adrian Leu and CHOP's Ethan Goldberg, Lei Zhou and Douglas Coulter.

The study appears in the journal Human Molecular Genetics.

To investigate the effects of missing this portion of DNA, more than 1 million base pairs long, the Penn team crossed existing mice that had particular deletions in their DNA to create a mouse that lacked the entire stretch that the human patients were missing. They quickly observed that all male mice died at birth due to respiratory failure. Females, who would have one normal X chromosome and one X chromosome with this missing stretch of genetic material, survived but had varying degrees of symptoms including epilepsy, cleft palate and other developmental problems.

"We believe this is because of skewed X chromosome inactivation," Wang said. "In females one of the X chromosomes' expression is randomly 'silenced' so that males and females have an equal dosage of genetic material from this sex chromosome under normal circumstances. In this case, if more female cells silence the X chromosome that has the deletion, the effects of the syndrome won't be as severe."

To narrow down which part of the deleted genetic material was responsible for the observed birth defects, the researchers genetically engineered one type of mice that lacked the first two-thirds of the original genetic deletion and another type that lacked the final third.

Unexpectedly, the mice lacking the two-thirds of the region on the X chromosome, which included 17 genes, did not display any respiratory failure, cleft palate or epilepsy.

"These mice were fine," Wang said. "It was very surprising to us that deleting this many genes on the X chromosome did not cause apparent problems for the mice."

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Link between missing DNA, birth defects confirmed