An uncommon mutation in the gene for the serotonin transporter protein may be a major contributor to neuropsychiatric disorders such as obsessive compulsive disorder, according to an article in the October 23rd issue of Molecular Psychiatry. According to the authors, obsessive compulsive disorder is 1 of the 10 leading causes of disability in the world.

Norio Ozaki, M.D., Ph.D., and his international team identified a mutation in the serotonin transporter gene, hSERT, in unrelated families affected by obsessive compulsive disorder. A second mutation within the same gene was found in some patients; correlation with clinical histories suggests that the presence of a double mutation results in a greater level of biochemical abnormality and more severe clinical symptoms.

"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 coauthor Dennis Murphy, M.D. "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 either obsessive compulsive disorder or obsessive compulsive personality disorder and some also had anorexia nervosa, Asperger's syndrome, social phobia, tic disorder, and alcohol or other substance abuse/dependence disorders.

Researchers found an unusual cluster of obsessive compulsive disorder, anorexia nervosa, and autism spectrum disorders together with the mutation in approximately 1 percent of individuals with OCD.

The scientists analyzed DNA from 170 unrelated individuals including 30 patients each with obsessive compulsive disorder, eating disorders, and seasonal affective disorder, plus 80 healthy control subjects. They detected gene variants by scanning the hSERT DNA sequence. An amino acid substitution (of Val425 for Ile425) occurred in 2 patients with obsessive compulsive disorder and their families, but not in additional patients or controls. Although the mutation is rare, it was found in 2 unrelated families, and the researchers propose it is likely to exist in other families affected by obsessive compulsive disorder and related conditions.

In addition to the noted mutation, the 2 original subjects and their 2 siblings had a particular form of another hSERT variation, two long alleles of the 5-HTTLPR polymorphism. This variation, associated with increased expression and function of the serotonin transporter, suggests 2 mutations within the same gene. The combination of these changes, both of which increase serotonin transport, may explain the unusual severity and refractory nature of the illnesses in these subjects and their siblings.

"This is a new model for neuropsychiatric genetics, the concept of 2 or maybe more within-gene modifications being important in each affected individual. This is also
probably the first report of a modification in a transporter gene resulting in a gain rather than a decrease in function," said Thomas Insel, M.D., Director of the National Institute of Mental Health.

Transporters have already been shown to be important sites for pharmacologic intervention for psychiatric disorders. Drugs that reduce the binding of serotonin to transporters (selective serotonin reuptake inhibitors, SSRIs) have been used with great success to treat mental disorders. According to the article, about one half of patients with obsessive compulsive disorder are treated with an SSRI agent, but the patients with the hSERT variation do not seem to respond to them.

Murphy noted that any vulnerability to obsessive compulsive disorder from gene effects most likely involve interaction with environmental factors such as stresses, gender, and treatments. By examining the serotonin transporter gene's mutation and flawed regulation in individuals with obsessive compulsive disorder, the new research provides insights on transporter function and on the consequences of mutation, which may lead to genetic tests to identify or treat psychiatric conditions.