Analysis of DNA samples from patients with obsessive compulsive disorder (OCD) and related illnesses suggests that these neuropsychiatric disorders affecting mood and behavior are associated with an uncommon mutant, malfunctioning gene that leads to faulty transporter function and regulation.

Researchers funded by the National Institutes of Health have found a mutation in the human serotonin transporter gene, hSERT, in unrelated families with OCD. A second variant in the same gene of some patients with this mutation suggests a genetic "double hit," resulting in greater biochemical effects and more severe symptoms. Among the 10 leading causes of disability worldwide, OCD is a mental illness characterized by repetitive unwanted thoughts and behaviors that impair daily life.

"In all of molecular medicine, there are few known instances where two variants within one gene have been found to alter the expression and regulation of the gene in a way that appears associated with symptoms of a disorder," said co-author Dennis Murphy, National Institute of Mental Health (NIMH) Laboratory of Clinical Science. "This step forward gives us a glimpse of the complications ahead in studying the genetic complexity of neuropsychiatric disorders."

Psychiatric interviews of the patients' families revealed that 6 of the 7 individuals with the mutation had OCD or OC personality disorder and some also had anorexia nervosa (AN), Asperger's syndrome (AS), social phobia, tic disorder, and alcohol or other substance abuse/dependence. Researchers found an unusual cluster of OCD, AN, and AS/autism, disorders together with the mutation in approximately one percent of individuals with OCD.

The scientists analyzed DNA from 170 unrelated individuals, including 30 patients each with OCD, eating disorders, and seasonal affective disorder, plus 80 healthy control subjects. They detected gene variants by scanning the hSERT gene's coding sequence. A substitution of Val425 for Ile425 in the sequence occurred in two patients with OCD and their families, but not in additional patients or controls. Although rare, with the I425V mutation found in two unrelated families, the researchers propose it is likely to exist in other families with OCD and related disorders.

In addition to the I425V mutation, the two original subjects and their two siblings had a particular form of another hSERT variant, two long alleles of the 5-HTTLPR polymorphism. This variant, associated with increased expression and function of the serotonin transporter, suggests a "double hit," or two changes within the same gene. The combination of these changes, both of which increase serotonin transport by themselves, may explain the unusual severity and treatment resistence of the illnesses in the subjects and their siblings.

SERT allows neurons, platelets, and other cells to accumulate the chemical neurotransmitter serotonin, which affects emotions and drives. Neurons communicate by using chemical messages like serotonin between cells. The transporter protein, by recycling serotonin, regulates its concentration in a gap, or synapse, and thus its effects on a receiving neuron's receptor.

Transporters are important sites for agents that treat psychiatric disorders. Drugs that reduce the binding of serotonin to transporters (selective serotonin reuptake inhibitors, or SSRIs) treat mental disorders effectively. About half of patients with OCD are treated with SSRIs, but those with the hSERT gene defect do not seem to respond to them, according to the study.

Any vulnerability to OCD from gene effects most likely interacts with events in the environment like stresses, other factors like gender, and treatments, Murphy said. By examining the serotonin transporter gene's mutation and flawed regulation in individuals with OCD, the new research provides insights on transporter function and on the consequences of the variant, which may lead to tests to identify and treat mental illness.