Clinical abnormalities in monoamine metabolism, in particular serotonin (5-HT) and dopamine have been implicated in the pathophysiology of many CNS-related disorders. Consistent with this, the use of drugs that block the effects of the serotonin transporter (5-HTT) and the dopamine transporter (DAT1) have pointed to these being candidate genes involved in a variety of disorders including Parkinson’s, Alzheimer’s, schizophrenia and psychiatric disorders. Clinical studies have suggested a polymorphism within intron 2 of the 5-HTT gene and the 3â untranslated region of the DAT1 gene are associated with the susceptibility to such disorders and can determine bioavailability of the DAT1 transporter in vivo (Battersby et al. 1997; Jacobsen et al. 2000). These polymorphisms are composed of a variable number of tandem repeats (VNTR) and the difference in copy number is correlated with predisposition to the disease. For example the 5-HTT transporter VNTR has 9, 10 or 12 copies of a 16 or 17 base pair element.

We have demonstrated that these VNTRs are functionally related, acting as transcriptional regulatory domains in reporter gene constructs both in vitro and in vivo. They support copy number dependent differential enhancer activity and additionally for the 5-HTT restricted neuronal regulation in the developing CNS in areas associated with endogenous 5-HTT expression (Fiskerstrand et al. 1999; MacKenzie & Quinn, 1999; Michelhaugh et al. 2001). Our data clearly indicate a potential mechanism by which such regulatory polymorphisms might influence physiology or susceptibility to disease by modulation of transporter gene expression.

We shall discuss both the variety of transcription factors that regulate these VNTR domains and how a base change within the tandem repeats can themselves change the transcriptional properties of the domain. The latter allows for a potentially greater degree of transcriptional plasticity directed from these domains than predicted for copy number alone. Thus clinical data correlating copy number alone of VNTRs with disease should be re-examined in light of these data to allow for such single base polymorphisms.

Related VNTRs, by primary sequence analysis, are found in several genes and we hypothesise that they are a novel class of regulatory domain that could determine both lineage expression and differential expression in vivo. Thus they act to regulate our normal physiology and their aberrant regulation could result in ‘abnormal’ behaviour.

I acknowledge the support of The Wellcome Trust and the MRC.

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