January 23, 2007
Scientists now possess the tools to detect a single variation in a gene’s DNA sequence and predict whether it will affect the chemical structure of its protein product. Still up in the air is the more complicated next step of explaining how nucleotide variations alter the biological function of the protein. In the December 22 issue of the journal Science, NIDCR grantees and colleagues provide an illuminating case study with the COMT gene.
The COMT gene encodes an enzyme of the same name involved in sensory signaling, or nociception. In previous work, the researchers showed that three common COMT gene haplotypes – a set of defined sequence variations - code for COMT enzymes with varying levels of activity that also correlate in people with a low, medium, and high sensitivity to pain and susceptibility to develop a chronic pain condition. Now, drilling down deeper for a biochemical explanation, the scientists report each COMT gene haplotype produces distinct structural modifications in the secondary structure of its mRNA that alter their rate of degradation and synthesis into protein. The secondary structure is the two-dimensional pairing of nucleotides within an RNA sequence that yields characteristic folds, stems, and loops that influence the rate of its translation into protein. According to the scientists, the low pain-sensitivity haplotype had the shortest stem loops in its secondary structure, while the high pain-sensitivity haplotype featured long, rigid stem loops that may hinder protein synthesis and reduce COMT’s enzymatic activity. Interestingly, by altering a single nucleotide in the mRNA of the high pain-sensitivity haplotype, the group was able to reconstruct short secondary structures similar to the low pain sensitivity haplotype. Taken together, these data suggest scientists now and in the future must consider not only the sequence of a gene but how the collective changes in that sequence might modify the secondary structure of mRNA and contribute to disease.