Defects in the interaction between the PRRT2 protein (green) and a protein called synapsin (red)
have been linked to infantile convulsions.

Photograph by James Maas

Locating a Genetic Glitch

International team finds gene responsible for rare movement disorder.

A team of 41 scientists led by HHMI investigator Louis Ptáček has pinpointed the gene responsible for a rare disease that causes sudden, uncontrollable movements. The culprit is a little known protein that may be responsible for communication between neurons.

Paroxysmal kinesigenic dyskinesia with infantile convulsions, or PKD/IC, is characterized by attacks of involuntary movements triggered when a person switches between voluntary movements—for example, a transition from sitting to standing or walking to running.

Ptáček, a researcher at the University of California, San Francisco, and collaborators from two dozen institutions in 10 countries sequenced the entire genomes of one member from each of six families with PKD/IC. All the individuals carried mutations in a gene called proline-rich transmembrane protein 2 or PRRT2. In a second analysis, the researchers found the same PRRT2 mutations in 24 of 25 families with PKD/IC. The vast majority of these mutations were truncating, meaning they shortened the PRRT2 protein they encode.

PRRT2 is normally found in the axons of nerve cells, but cells expressing mutant PRRT2 had almost no protein in their axons. As a result, the researchers theorize that individuals with PKD/IC have hyperexcitable nerve cells that cause the sudden movements. They published their findings January 26, 2012, in the inaugural issue of Cell Reports.

The scientists also found that PRRT2 interacts with a protein called SNAP25, which is involved in signaling between nerve cells. SNAP25 plays a role in helping synaptic vesicles dock to the cell membrane and empty their contents into the junction between nerve cells. This finding suggested to the researchers that people with PKD/IC may have defects in signaling between their brain cells. Ptáček found further support for this idea when he discovered that a protein that causes a related disease called paroxysmal nonkinesigenic dyskinesia, or PNKD, regulates neuronal signaling. He plans to test this hypothesis by engineering mice that lack the PRRT2 protein.

New treatments aren’t necessary for PKD/IC can easily be controlled with existing drugs, but Ptáček’s findings could pave the way for new therapies for more common forms of movement disorders, such as those in Huntington’s and Parkinson’s diseases.