Researchers have discovered a gene called PHF21A, whose mutation results in malformed faces and skulls, as well as mental retardation.

The finding was published in The American Journal of Human Genetics and was conducted by Dr. Hyung-Goo Kim, molecular geneticist at the Medical College of Georgia at Georgia Health Sciences University and his team.

The researchers discovered the PHG21A mutated gene in patients with Potocki-Shaffer syndrome, a rare disorder that can result in significant abnormalities, like a small head and chin as well as intellectual disability.

The researchers conducted experiments in zebrafish, which developed similar head and brain abnormalities to those found in humans and discovered that their findings were confirmed when they suppressed the PHF21A gene in zebrafish.

Dr. Kim explained: “With less PHF21A, brain cells died, so this gene must play a big role in neuron survival.”

To reconfirm their finding, the team inserted the gene back into the malformed fish, which subsequently became normal. The gene was also found in the craniofacial area of normal mice. Even though it is impossible to cure humans just by re-inserting the normal gene as is possible in zebrafish, the researchers believe that their finding will, in the future, allow genetic screening and possibly early intervention during fetal development, as well as treatments to increase PHF21A levels. In addition, the finding provides more insight into a better understanding of face, skull and brain formation.

The team focused on the gene when they used a distinctive chromosomal break found in patients with Potocki-Shaffer syndrome as a starting point. Chromosomes, i.e. packages of DNA and protein, are not supposed to break. However, when they do, they can damage nearby genes. Co-author of the study, Dr. Lawrence C. Layman, who is Chief of the MCG Section of Reproductive Endocrinology, Infertility and Genetics, explained: “We call this breakpoint mapping and the breakpoint is where the trouble is.”

Damaged genes can no longer retain their optimum function. In PHF21A’s case for instance the functionality is reduced to about half of the norm.

Layman continues: “When you see the chromosome translocation, you don’t know which gene is disrupted. You use the break as a focus then use a bunch of molecular techniques to zoom in on the gene.”

Dr. Kim added that although the reasons for chromosomal breaks remain unknown, they are probably environmental and/or genetic.

Researchers had little knowledge about PHF21A other than its function in determining how tightly DNA is wound in histones, i.e. packages of proteins. A transcription factor, sometimes called a sequence-specific DNA-binding factor, is a protein that binds to specific DNA sequences, and how tightly DNA is wound, determines whether the transcription factors have the necessary access to regulate gene expression. Controlling the gene expression is an important factor, as some genes need to be expressed only at a specific time or tissue. The researchers believe that PHF21A’s primary function is to suppress other genes. For instance, in ensuring that genes, which should only be expressed in brain cells do not appear in other types of cells.

Future research includes identifying other ‘depressor’ genes regulated by PHF21A by using the gene as a geographic positioning system as well as screening patients for mutations of those genes.

Layman said:

“We want to find other people with different genes causing the same problem.” The researchers hypothesize that the genes, which interact with PHF21A or are regulated by the gene are the most likely candidates. Kim commented that it is too early to know what percentage of Potocki-Shaffer syndrome patients have the PHF21A mutation, and Layman added: “Now that we know the causative gene, we can sequence the gene in more patients and see if they have a mutation.”

They also intend to explore less-severe forms of mental deficiency for perhaps milder mutations of the gene, such as autism. According to Kim, over a dozen of the 25,000 human genes are known to cause craniofacial defects and mental retardation that often occur simultaneously.

Written by Petra Rattue