Levels of Formerly Silent Genes in Prader-Willi Syndrome Restored in Lab

A team of researchers was able to restore the normal level of genes that are usually silenced in Prader-Willi syndrome (PWS) in patient neurons grown in the lab.

The study, led by researchers at the University of Connecticut, is titled “Zinc finger protein 274 regulates imprinted expression of transcripts in Prader-Willi syndrome neurons,” and was published in the journal Human Molecular Genetics.

The study was funded by the Foundation for Prader-Willi Research, the Cascade Fellowship, and the Connecticut Regenerative Medicine Research Fund.

PWS is a complex genetic disorder that causes an excessive appetite resulting in obesity, and cognitive and behavior disabilities. People with Prader-Willi never feel full and can’t control their desire to eat. The condition affects an estimated 1 in 10,000 to 1 in 30,000 people worldwide.

The disorder is caused by the deletion or loss of function in a gene at a certain region of chromosome 15. Normally, people inherit one copy of each chromosome from their mother and another copy from their father, but certain genes in chromosome 15 are silenced on the maternal side and active only on the father’s side.

In about 70 percent of Prader-Willi syndrome patients, the genes needed are deleted from the paternal copy of chromosome 15. A fewer number of patients, about 25 percent, inherited the two gene copies from their mother and none from their father. These are considered spontaneous genetic genetic errors that take place near the time of conception.

In very rare cases, the child inherits a genetic mutation from parents who don’t have the disease. When this happens, several siblings may be born with the PWS.

Since the genes involved in Prader-Willi are silent on the mother’s side, patients have abnormally low levels of these genes. This means that PWS patients usually have the correct genes available, but since they are silent, their levels are lower than they should be and are non-functioning.

The UConn researchers wanted to see whether it was possible to reverse the silent maternal genes and recover their function, in effect repairing the genes causing Prader-Willi syndrome.

They had previously discovered that the ZNF274 protein, which binds to DNA, appeared to be solely involved in the process of silencing the maternal gene copy.

Researchers collected pluripotent stem cells – cells that can give rise to many different types of cells – from Prader-Willi patients. Using these cells, they deleted the ZNF274 protein and then grew them into brain neurons in the lab.

Neurons without the ZNF274 protein (called knockout) looked normal and started to express the maternal genes that were previously silent in Prader-Willi patients, restoring the genes back to normal levels.

“The activation of normally silent maternal PWS neuronal transcripts in our stem cell knockout model [in the lab] suggests that ZNF274 is a potential target for future therapeutic application in PWS,” researchers wrote.

But more studies are required.

“We still need to figure out if knocking out ZNF274 is doing anything else,” possibly something that could be harmful to people, Maeva Langouët, first author of the study, said in a UConn news story.

Langouët believes that in the future, a new line of research based on ZNF274 may offer hope, and potentially a therapeutic approach, for children with Prader-Willi syndrome.