SLC6A3

At least 19 mutations in the SLC6A3 gene have been identified in people with dopamine transporter deficiency syndrome, a rare movement disorder that worsens over time. Its signs and symptoms usually begin in infancy but can appear in childhood or later. Some of the mutations change single protein building blocks (amino acids) in the dopamine transporter protein. Others lead to the production of an abnormally short protein or prevent cells from producing any functional protein. All of these mutations impair the function of the dopamine transporter. Because the impaired transporter cannot carry dopamine out of the synaptic cleft and back into neurons, dopamine builds up in the spaces around neurons. The excess dopamine alters signaling between neurons and may suppress (inhibit) pathways that normally trigger the production of more dopamine. Although dopamine has a critical role in controlling movement, it is unclear how altered dopamine signaling causes the specific movement abnormalities found in people with dopamine transporter deficiency syndrome.

Studies suggest that the age at which signs and symptoms appear is related to how severely the function of the dopamine transporter is affected. Affected individuals who develop movement problems starting in infancy most often have transporter activity that is less than 5 percent of normal. Those whose movement problems appear in childhood or later tend to have somewhat higher levels of transporter activity, although they are still lower than normal. Researchers speculate that higher levels of transporter activity may delay the onset of the disease in these individuals.

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Variations (polymorphisms) in the SLC6A3 gene have been studied as possible risk factors for attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). ADHD, which typically begins in childhood, is characterized by overactivity, impulsive behavior, and difficulty paying attention. ASD represents a group of developmental conditions that affect communication and social interaction. Changes in dopamine signaling appear to play an important role in both ADHD and ASD. However, it is unclear how variations in the SLC6A3 gene may be involved. Multiple genetic and environmental factors, most of which remain unknown, likely determine the risk of developing these complex conditions.