A gene whose mutation results in malformed faces and skulls as well as mental retardation has been found by scientists.
They looked at patients with Potocki-Shaffer syndrome, a rare disorder that can result in significant abnormalities such as a small head and chin and intellectual disability, and found the gene PHF21A was mutated, said Dr. Hyung-Goo Kim, molecular geneticist at the Medical College of Georgia at Georgia Health Sciences University.
The scientists confirmed PHF21A's role by suppressing it in zebrafish, which developed head and brain abnormalities similar to those in patients. "With less PHF21A, brain cells died, so this gene must play a big role in neuron survival," said Kim, lead and corresponding author of the study published in The American Journal of Human Genetics. They reconfirmed the role by giving the gene back to the malformed fish - studied for their adeptness at regeneration - which then became essentially normal. They also documented the gene's presence in the craniofacial area of normal mice.
While giving the normal gene unfortunately can't cure patients as it does zebrafish, the scientists believe the finding will eventually enable genetic screening and possibly early intervention during fetal development, including therapy to increase PHF21A levels, Kim said. It also provides a compass for learning more about face, skull and brain formation.
The scientists zeroed in on the gene by using a distinctive chromosomal break found in patients with Potocki-Shaffer syndrome as a starting point. Chromosomes - packages of DNA and protein - aren't supposed to break, and when they do, it can damage genes in the vicinity.
"We call this breakpoint mapping and the breakpoint is where the trouble is," said Dr. Lawrence C. Layman, study co-author and Chief of the MCG Section of Reproductive Endocrinology, Infertility and Genetics. Damaged genes may no longer function optimally; in PHF21A's case it's about half the norm.
"When you see the chromosome translocation, you don't know which gene is disrupted," Layman said. "You use the break as a focus then use a bunch of molecular techniques to zoom in on the gene." Causes of chromosomal breaks are essentially unknown but likely are environmental and/or genetic, Kim said.