Yale Bulletin and Calendar

November 7, 2003|Volume 32, Number 10

Rare form of obsessive compulsive
disorder is linked to gene mutation

A rare form of obsessive-compulsive disorder (OCD) is associated with an uncommon gene mutation, according to Yale and National Institutes of Mental Health (NIMH) researchers.

The findings are the strongest evidence to date that neuropsychiatric disease can result from mutations in neuronal proteins.

Dennis Murphy and colleagues at NIMH conducted the research with Gary Rudnick, professor of pharmacology at Yale School of Medicine, and Fusun Kilic, also of Yale. The studies appeared in Molecular Psychiatry on Oct. 23 and in Molecular Pharmacology in August.

"There are not a lot of established connections between genes and behavior, especially abnormal behavior," Rudnick says. "Our finding focuses on the serotonin transporter for mood and behavior and ties it to a specific behavioral disorder. This transporter is a target for cocaine, amphetamines and ecstasy, in addition to anti-depressant drugs."

Serotonin is found throughout the body, particularly in the brain, where it acts as a neurotransmitter. It is released from one nerve cell into a synapse, or space, between nerves, then interacts with receptors on the surface of another cell to transmit the signal. When serotonin is released, the human serotonin transporter, hSERT, is responsible for removing serotonin from the synapse by transporting it back into the cell. Some anti-depressant drugs, used to treat neuropsychiatric disorders such as affective disorder, anxiety disorders, OCD and autism, inhibit hSERT re-uptake of serotonin in the brain.

Murphy's group at NIMH discovered that a small group of patients with OCD carried a mutation in the serotonin transporter gene. DNA samples taken from two unrelated families with OCD found half had mutations, and did not respond to drugs designed to inhibit hSERT activity.

Rudnick's group measured the activity of the mutant protein and found that the mutant protein was better than the normal protein at transporting serotonin. Usually mutations interfere with function. They demonstrated that this mutation increased the transport activity of the neuronal protein due to a defect in the regulation of hSERT.

Rudnick says following up on these findings might lead to a better understanding of the way most OCD cases develop and how medications affecting hSERT might be used in their treatment. He says it also might offer insight into how mood-altering drugs work.

-- By Jacqueline Weaver

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