Penn Vet-CHOP research sheds light on birth defects

Each year in the United States, about 2,600 babies are born with cleft palates, roughly 150,000 people are diagnosed with epilepsy, and nearly half a million babies are born preterm, which puts them at risk of respiratory failure.

New insight from a study by researchers at the School of Veterinary Medicine and the Children’s Hospital of Philadelphia (CHOP), published in the journal Human Molecular Genetics, has laid the groundwork for developing diagnostic tools and therapies for these all-too-common conditions.

The Penn Vet-CHOP team—co-led by Jeremy Wang, a professor of developmental biology in Penn Vet’s Department of Animal Biology, and Jian Zhou, a postdoctoral researcher—began the study after reading about a mother and her young daughter who both possessed a suite of physical maladies, including cleft palate and epilepsy. The mother had also previously lost a 2-week-old son to respiratory failure.

Baby Preemie

Each year in the United States, nearly half a million babies are born preterm, which puts them at risk of respiratory failure.

An Italian research team discovered that the mother and daughter were both missing more than 1 million base pairs of their genetic code, but the scientists could not definitively show that the genetic deletion was the cause of the family’s troubles.

Picking up where the Italian team left off, the Penn team was able to breed a line of mice that lacked the same exact region of DNA that was missing in the human patients. Sure enough, the male mice all died soon after birth due to respiratory failure and the female mice suffered from seizures, developmental delays, and cleft palates.

“This study has demonstrated that deleting this region in mice causes them to respond like humans with the same deletion,” says Wang. “Now that we have a mouse model, we can try to genetically pinpoint which genes are responsible.”

To do this, Wang, Zhou, and colleagues bred two additional lines of mice. One was missing the first two-thirds of the original deletion and the other lacked only the final third, about 350 kilobasepairs (kbp). To the researchers’ surprise, the mice missing the larger chunk of DNA appeared normal, while the mice with the smaller deletion had the same symptoms as animals missing the full stretch of DNA.

This 350 kbp region contains four genes that are also present in humans, leading the researchers to believe that it is the lack of one or more of these genes that leads to the problems seen in both mice and humans.

“Finding the causative genes for these conditions could have some very clinically important implications,” Wang says, including prenatal testing and even therapies to “make up” for the missing gene product.

Originally published on March 13, 2014