Serotonin Transporter: Gene, Genetic Disorders, and Pharmacogenetics
Dr. Murphy, et al. published an article in 2004 named Serotonin Transporter: Gene, Genetic Disorders, and Pharmacogenetics; the studies within that journal article are the discussion of this blog. Serotonin transporter helps transport serotonin into neurons, enterchromaffin cells, platelets, and other cells (Murphy, 2004). It re-uptakes and reuses serotonin after neural stimulation. Serotonin is a neurotransmitter that helps maintain mood, digestion and appetite, sleep, memory, and many other things mostly found in the brain and intestines. The serotonin transporter gene spans 37.8 kb on chromosome 17q11.2. Studies primarily look at polymorphisms on the 5HTTLPR region of repeated elements; this variable tandem repeat is about 1.4 kb upstream and near exon two, shown in Figure 1. The most common composition is fourteen (short, S) or sixteen (long, L) repeated elements. The L variant has high antidepressant efficacy. In some cases super long 5HTTLPR causes sudden infant death syndrome and OCD. Mice with genetically reduce or absent SERT had low antidepressant effectiveness. The S variant is associated with lower expression of the SERT, and so an SS 5HTTLPR genotype has poorer antidepressant responses and more considerable side effects. Genotyping of a patient before care would help improve drug treatments.
Figure 2 demonstrates the homology present in the SERT gene between ten species. There is also high sequence homology with the dopamine transporter (DAT) and norepinephrine transporter (NET). There is over 90% homology in vertebrates and lesser in insects and worms (Murphy, 2004). In the SERT TM8 region there is an isoleucine 425 valine mutation that is highly conserved of the transmembrane region. This missense mutation was recently detected in family members with obsessive compulsive disorder, and others like Asperger’s syndrome, social phobia, anorexia nervosa, tic disorder, depression, and alcohol abuse (Murphy, 2004). The mutation modifies the alpha helix and therefore function of the transporter. Both mutations in the I425V and LL 5HTTLPR direct towards more significant expression, function, and interactions. Interaction of two or more mutations should be considered but leads to more complex clinical trials.
Studies of SERT in the brain use positron emission tomography (PET) to visualize SERT activity. SERT is confirmed by a serotonin re-uptake inhibitors (SRIs) antagonist, most popularly used is DASB because of its good penetration of the blood brain barrier. Images of PET displaying SERT function can be seen in Figure 3. SRIs can work as antidepressants and in treatment of OCD. Studies are done on SRI metabolizing enzymes, like CYP2D6. Gene variants of CYP2D6 cause slow or ultra-rapid metabolism of SRIs in patients that needs to be monitored for toxicity and/or under dosing (Murphy, 2004). Overall, genetic polymorphisms in the 5HTTLPR can lead to developmental disorders, or other complex disorders like poly-substance abuse, irritable bowl syndrome, primary pulmonary hypertension, and myocardial infarction. Variations in length of the 5HTTLPR and other mutations transform the function of SERT and should be taken into consideration when finding treatment for a patient. Also under consideration should be environmental interactions and epistatic genes. These studies will be useful in innovating the pharmacogenomics field.
Citations
Murphy, D. L., et al. (2004, April). Serotonin Transporter: Gene, Genetic Disorders, and Pharmacogenetics. Molecular Interventions, 4(2), 109-123. doi:10.1124/mi.4.2.8