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 gene mutation that leads to faulty transporter function and regulation, according to a report in the October 23, 2003, Molecular Psychiatry.

The researchers found a mutation in the human serotonin transporter gene, hSERT, in unrelated families with obsessive compulsive disorder. 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.

“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 study coauthor Dennis Murphy, MD, of the 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.”

GENETICS AND PERSONALITY

Psychiatric interviews of the patients’ families revealed that six of the seven individuals with the mutation had 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. The researchers reported an unusual cluster of obsessive compulsive disorder, anorexia, and Asperger’s syndrome/autism disorders together with the mutation in approximately 1% of individuals with obsessive compulsive disorder.

The investigators 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 gene’s coding sequence. A substitution of Val425 for Ile425 in the sequence occurred in two patients with obsessive compulsive disorder and their families, but not in additional patients or controls. Although rare, with the I425V mutation found in two unrelated families, the researchers proposed it is likely to exist in other families with obsessive compulsive disorder and related disorders.

DOUBLE HIT

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.

“This is a new model for neuropsychiatric genetics, the concept of two 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 NIMH Director Thomas R. Insel, MD.

PSYCHIATRIC IMPLICATIONS

Serotonin transporters allow neurons, platelets, and other cells to accumulate the chemical neurotransmitter serotonin, which affects emotions and drives. While drugs that reduce the binding of serotonin to transporters (selective serotonin reuptake inhibitors, or SSRIs) treat mental disorders effectively, patients with obsessive compulsive disorder and the hSERT gene defect do not seem to respond to treatment with SSRIs, according to the study.

Any vulnerability to obsessive compulsive disorder from genetic effects most likely interacts with events in the environment like stresses, other factors like gender, and treatments, Dr. Murphy said. 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 the variant, which may lead to tests to identify and treat mental illness.

Suggested Reading
Ozaki N, Goldman D, Kaye WH, et al. Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype. Mol Psychiatry. 2003;8:933-936.

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