Link Discovered between WRP Gene and Severe Mental Retardation

February 21, 2011

Researchers at Duke University Medical Center have made a possible connection between the gene known as WRP and a form of mental retardation.

Recently, researchers at Duke University Medical Center have made a possible connection between the gene known as WRP and a form of human mental retardation.

This connection was revealed through the exploration of the function of this gene, which controls how neurons develop new connections. The finding may also provide insights into a form of human mental retardation, as the gene is linked to memory and learning.

The study was originally published in the Journal of Neuroscience.

Mice were used to investigate the functions of the gene WRP in the brain cell. Then these results were verified and tested to see how severely memory and learning are affected when WRP is missing.

"Human genomics studies have opened the floodgates of information that will benefit people with many different diseases," said Scott Soderling, an assistant professor in the Duke Department of Cell Biology. "But it is impossible to correct something without knowing what the exact underlying problem is."

The scientists were aware of the possible link between severe mental retardation and the disruption of WRP from previous human research into the genetics of one individual.

The researchers performed experiments using neuronal cells in a lab dish which demonstrated that cells enhanced with WRP formed many filopodia, tentacle-like protuberances which neurons use to connect with one another.

Neurons missing WRP were defective and could not make filopodia, which meant they could not make the correct number of connections, called synapses.

In studies on mice enriched with and missing WRP, the researchers were able to see behavior differences.

In one experiment, they tested normal and mice missing the gene WRP for their behavior in recognizing a previously unseen toy versus a familiar toy.

A mouse with WRP will usually spend less time investigating a toy it has seen before, but the mice without WRP spent the same amount of time with each toy, suggesting they don't remember the toy they saw yesterday.

"There was a striking difference between the groups of mice," said Soderling, who is part of the Neonatal Perinatal Research Institute. "The mice without WRP had difficulty learning and didn't display typical memory ability in several experiments."

"Because the excitatory synapses that we are studying form their connections right after birth in humans, we think these specific pathways may even provide an opportunity for early intervention after birth," Soderling said. "Abnormalities in these types of synapses have been linked to mental retardation, and also to schizophrenia and fetal alcohol syndrome, where there are abnormalities that could later affect learning and memory."

"What surprised me most is that we had a preconceived notion that WRP would be part of a process that helped the neuronal cell surface fold inward," said lead author Benjamin Carlson, a graduate student in the Soderling lab. "Eventually we figured out it was just the opposite. When we placed the WRP protein on the inside of the neurons, we could see these buds forming out of the neurons, which then became the longer filopodia and synapses. It is rewarding when you finally think through the possibilities and take a different approach that turns out to yield something valuable."