Variants in the 3’ untranslated region of the KCNQ1-encoded Kv7.1

Summary

We hypothesized that single nucleotide polymorphisms (SNPs) in the 3’untranslated region (3’UTR) can drive the increased or decreased translation of one allele over the other. This is of clinical relevance when one of the two alleles harbors a disease-causing mutation. Changing the relative expression of the normal allele versus the mutation-containing allele alters the balance between normal and mutant proteins. SNPs in the 3'UTR may alter this balance as they are frequent and often heterozygous. MicroRNAs bind the 3’UTR to inhibit translation of the messenger-RNA to protein. 3’UTR SNPs can alter microRNA binding and thereby alter inhibition of the allele on which they reside.

In the attached research article, we showed the first evidence for this mechanism in long QT syndrome: SNPs in the 3’UTR of the KCNQ1 gene repress translation by creating binding sites for a cardiac microRNA. These suppressive SNPs largely determined the severity of the long QT syndrome in carriers of a KCNQ1 mutation. When the suppressive SNPs reside on the normal KCNQ1 allele, the normal allele is repressed and there is clear clinical manifestation of the mutation. However, when the suppressive SNPs reside on the mutant KCNQ1 allele, this mutant allele is repressed and there are hardly clinical manifestations of the mutation.

Conclusion:

These initial findings suggest that 3’UTR SNPs can alter microRNA binding and thereby modulate expression of a disease-causing mutation. This study uncovers a novel mechanism that explains why one single mutation can present such profound differences in disease severity. It is intriguing that our findings show that disease severity can be altered by the unaffected ‘married-in’ parent. ‘MicroRNAgenetics’ therefore become highly relevant and open novel ways to understand why genetic heart disease varies in its clinical manifestation.