Gene promoter analysis in molecular diagnostics: do or don’t?

Abstract

Approximately 1% of single basepair substitutions causing human genetic disease occur within gene promoter regions where they disrupt the normal processes of gene activation and transcriptional initiation, and usually decrease or increase the level of mRNA and, thus, protein [1]. Although promoter mutations are known to have functionally important consequences for gene expression, promoter analysis is not a regular part of molecular diagnostics. One reason is that the effect of promoter mutations can be very subtle. For instance, the majority of missense mutations cause a fairly easy to identify qualitative defect. By contrast, promoter mutations may cause small quantitative defects that may be hard to detect. Even if the promoter of an autosomal gene is completely downregulated as result of mutation, half of the normal amount of protein is present, which is often enough to prevent severe disease. Another reason for not performing promoter analysis is that it is complex and the assays that are needed to investigate the functional relationship between the mutation and disease are laborious and difficult to perform. As a result, thorough studies of promoter mutations are scarce and often confined to research laboratories. By contrast, in epidemiological studies in which large amounts of single-nucleotide polymorphisms (SNPs) are studied in relation to disease, several promoter SNPs have recently been shown to be associated with specific diseases. Unfortunately, appropri ate functional analysis of these SNPs is often lacking and it can be questioned if they are themselves causing disease. Gene promoter mutations