Promoter polymorphisms and function

Many polymorphisms have been reported in the coding region of GPCRs and some are correlated with disease states such as the association between polymorphisms of the 5HT2A gene and psychiatric disorders (Arranz etal. 2001). Thus far relatively few have been recorded in potential regulatory regions. It is unlikely that SNPs are not present in regulatory regions of GPCR genes since, on average a SNP is present every 2 kb of the human genome. Whereas it is possible that SNPs in regulatory regions are relatively rare and probable that most are benign, their apparent absence is more likely a reflection of the fact that, in most cases, only ORFs have been searched for SNPs—if you lose your keys on a dark street, you tend to search first under the street light. Alternatively, SNPs that map to transcription factor ORFs may have an indirect effect on transcription of their target GPCR genes. An example is provided by mutations of the retina-specific homeobox gene, Crx, that regulates opsin expression and mutations of which are associated with retinal degenerative disorders including autosomal dominant cone-rod dystrophy, dominant retinitis pigmentosa and Leber congenital amaurosis (Sohocki etal. 1998).

One study of the human ^-adrenergic receptor revealed eight polymorphisms within a 1.5 kb region upstream of the start codon. Two of these halotypes showed diminished transcription (Scott et al. 1999). However, no association has been found between

^-adrenergic receptor promoter polymorphisms and hypertension (Kato et al. 2001). Several studies have tested the linkage between polymorphisms in the promoter of the alpha2A adrenergic receptor and mood disorders and schizophrenia, but again no association of polymorphism and behaviour has been observed (Ohara et al. 1998; Tsai etal. 2001).

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